Reddy ST


Full name : Reddy Srinivasa T

First name : Srinivasa T

Mail : Divisions of Cardiology, Atherosclerosis Research Unit, University of California, Los Angeles School of Medicine, Los Angeles, CA

Zip Code :

City :

Country : USA

Email :

Phone :

Fax :

Website :

Directory :

References (38)

Title : Apolipoprotein A-I mimetics mitigate intestinal inflammation in COX2-dependent inflammatory bowel disease model - Meriwether_2019_J.Clin.Invest_129_3670
Author(s) : Meriwether D , Sulaiman D , Volpe C , Dorfman A , Grijalva V , Dorreh N , Solorzano-Vargas RS , Wang J , O'Connor E , Papesh J , Larauche M , Trost H , Palgunachari MN , Anantharamaiah GM , Herschman HR , Martin MG , Fogelman AM , Reddy ST
Ref : J Clinical Investigation , 129 :3670 , 2019
Abstract : Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2 KO but not WT mice. Cox2 MKO increased pro-inflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2 MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, while administration of an LXA4 analog rescued disease in Cox2 MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2 MKO/CCHF and piroxicam-accelerated Il10-/- models of inflammatory bowel disease (IBD) and reduced elevated levels of pro-inflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2 MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides: i) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (oxPAPC) dependent pro-inflammatory responses in human macrophages and intestinal epithelium; and ii) directly cleared pro-inflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for pro-inflammatory and inflammation resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.
ESTHER : Meriwether_2019_J.Clin.Invest_129_3670
PubMedSearch : Meriwether_2019_J.Clin.Invest_129_3670
PubMedID: 31184596

Title : Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis - Charles-Schoeman_2013_Arthritis.Rheum_65_2765
Author(s) : Charles-Schoeman C , Lee YY , Shahbazian A , Gorn AH , FitzGerald J , Ranganath VK , Taylor M , Ragavendra N , McMahon M , Elashoff D , Reddy ST
Ref : Arthritis Rheum , 65 :2765 , 2013
Abstract : OBJECTIVE: To investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA).
METHODS: The relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients.
RESULTS: Paraoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05). CONCLUSION: The current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA.
ESTHER : Charles-Schoeman_2013_Arthritis.Rheum_65_2765
PubMedSearch : Charles-Schoeman_2013_Arthritis.Rheum_65_2765
PubMedID: 23917967

Title : Role of PON2 in innate immune response in an acute infection model - Devarajan_2013_Mol.Genet.Metab_110_362
Author(s) : Devarajan A , Bourquard N , Grijalva VR , Gao F , Ganapathy E , Verma J , Reddy ST
Ref : Mol Genet Metab , 110 :362 , 2013
Abstract : N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) is a quorum-sensing molecule produced by gram-negative microbial pathogens such as Pseudomonas aeruginosa (PAO1). 3OC12-HSL is involved in the regulation of bacterial virulence factors and also alters the function of the host immune cells. Others and we have previously shown that paraoxonase 2 (PON2), a member of the paraoxonase gene family expressed in immune cells, hydrolyzes 3OC12-HSL. In this study, we examined i) whether macrophage PON2 participates in 3OC12-HSL hydrolysis, ii) the effect of PON2 deficiency in acute PAO1 infection in mice and iii) the effect of 3OC12-HSL on PON2 deficient (PON2-def) macrophages. When compared to wild type macrophages, both intact cells and membrane-enriched protein lysates obtained from PON2-def macrophages show a marked impairment in their ability to hydrolyze 3OC12-HSL. PON2 expression (message and protein) is not altered in response to 3OC12-HSL in macrophages. 3OC12-HSL treated PON2-def macrophages showed i) an increase in ER stress and oxidative stress, ii) defective phosphatidylinositol 3-kinase (PI3 kinase)/AKT activation, and iii) reduced phagocytosis function. Moreover, the nitration to phosphorylation ratio of Tyr458 in p85 protein, the regulatory subunit of PI3-kinase that has been correlated with the phagocytosis function of macrophages, was increased in PON2-def macrophages. Antioxidant treatment reversed the effects of PON2 deficiency in macrophage phagocytosis function. Furthermore, following administration of 1.6x10(7) CFU of PAO1, bacterial clearance was significantly reduced in the lungs (5.7 fold), liver (2.5 fold), and spleen (14.8 fold) of PON2-def mice when compared to wild type mice. Our results suggest that PON2 plays an important role in innate immune defense against PAO1 infection.
ESTHER : Devarajan_2013_Mol.Genet.Metab_110_362
PubMedSearch : Devarajan_2013_Mol.Genet.Metab_110_362
PubMedID: 23911207

Title : PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death - Schweikert_2012_Cell.Death.Differ_19_1549
Author(s) : Schweikert EM , Devarajan A , Witte I , Wilgenbus P , Amort J , Forstermann U , Shabazian A , Grijalva V , Shih DM , Farias-Eisner R , Teiber JF , Reddy ST , Horke S
Ref : Cell Death Differ , 19 :1549 , 2012
Abstract : To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death.
ESTHER : Schweikert_2012_Cell.Death.Differ_19_1549
PubMedSearch : Schweikert_2012_Cell.Death.Differ_19_1549
PubMedID: 22441669

Title : Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis - Charles-Schoeman_2012_Ann.Rheum.Dis_71_1157
Author(s) : Charles-Schoeman C , Lee YY , Grijalva V , Amjadi S , FitzGerald J , Ranganath VK , Taylor M , McMahon M , Paulus HE , Reddy ST
Ref : Ann Rheum Dis , 71 :1157 , 2012
Abstract : OBJECTIVES: Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls.
METHODS: HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDL's antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay.
RESULTS: Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2% +/- 11.1%) and controls (39.5% +/- 8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=-0.39, p=0.01) and erythrocyte sedimentation rate, (r=-0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDL's ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=-0.34, p=0.03).
CONCLUSIONS: The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDL's antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.
ESTHER : Charles-Schoeman_2012_Ann.Rheum.Dis_71_1157
PubMedSearch : Charles-Schoeman_2012_Ann.Rheum.Dis_71_1157
PubMedID: 22267330

Title : D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice - Navab_2012_J.Lipid.Res_53_437
Author(s) : Navab M , Reddy ST , Anantharamaiah GM , Hough G , Buga GM , Danciger J , Fogelman AM
Ref : J Lipid Res , 53 :437 , 2012
Abstract : To test the hypothesis that intestine is a major site of action for D-4F, LDLR(-/-) mice were fed a Western diet (WD) and administered the peptide subcutaneously (SQ) or orally. Plasma and liver D-4F levels were 298-fold and 96-fold higher, respectively, after SQ administration, whereas peptide levels in small intestine only varied by 1.66 +/- 0.33-fold. Levels of metabolites of arachidonic and linoleic acids known to bind with high affinity to D-4F were significantly reduced in intestine, liver and hepatic bile to a similar degree whether administered SQ or orally. However, levels of 20-HETE, which is known to bind the peptide with low affinity, were unchanged. D-4F treatment reduced plasma serum amyloid A (SAA) and triglyceride levels (P < 0.03) and increased HDL-cholesterol levels (P < 0.04) similarly after SQ or oral administration. Plasma levels of metabolites of arachidonic and linoleic acids significantly correlated with SAA levels (P < 0.0001). Feeding 15-HETE in chow (without WD) significantly increased plasma SAA and triglyceride levels and decreased HDL-cholesterol and paraoxonase activity (P < 0.05), all of which were significantly ameliorated by SQ D-4F (P < 0.05). We conclude that D-4F administration reduces levels of free metabolites of arachidonic and linoleic acids in the small intestine and this is associated with decreased inflammation in LDL receptor deficient mice.
ESTHER : Navab_2012_J.Lipid.Res_53_437
PubMedSearch : Navab_2012_J.Lipid.Res_53_437
PubMedID: 22167743

Title : Macrophage paraoxonase 2 regulates calcium homeostasis and cell survival under endoplasmic reticulum stress conditions and is sufficient to prevent the development of aggravated atherosclerosis in paraoxonase 2 deficiency\/apoE-\/- mice on a Western diet - Devarajan_2012_Mol.Genet.Metab_107_416
Author(s) : Devarajan A , Grijalva VR , Bourquard N , Meriwether D, 3rd , Imaizumi S , Shin BC , Devaskar SU , Reddy ST
Ref : Mol Genet Metab , 107 :416 , 2012
Abstract : Paraoxonase 2 deficiency (PON2-def) alters mitochondrial function and exacerbates the development of atherosclerosis in mice. PON2 overexpression protects against ER stress in cell culture. In this paper, we examined the role of PON2 in the unexplored link between ER stress and mitochondrial dysfunction and tested whether restoration of PON2 in macrophages is sufficient to reduce aggravated atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. ER stress response genes, intracellular calcium levels, and apoptotic nuclei were significantly elevated in PON2-def/apoE(-/-) macrophages compared to apoE(-/-) macrophages in response to ER stressors, but not at the basal level. In contrast, PON2-def/apoE(-/-) macrophages exhibited greater mitochondrial stress at the basal level, which was further worsened in response to ER stressors. There was no difference in ER stress response genes and apoptotic nuclei between apoE(-/-) and PON2-def/apoE(-/-) macrophages when pretreated with xestospongin (which blocks the release of calcium from ER) suggesting that PON2 modulates cell survival and ER stress by maintaining calcium homeostasis. Treatment with a mitochondrial calcium uptake inhibitor, RU360, attenuated ER stressor mediated mitochondrial dysfunction in PON2-def/apoE(-/-) macrophages. CHOP expression (ER stress marker) and apoptotic nuclei were significantly higher in aortic lesions of PON2-def/apoE(-/-) mice compared to apoE(-/-) mice fed a Western diet. Restoration of PON2 in macrophages reduced ER stress, mitochondrial dysfunction and apoptosis in response to ER stressors. Furthermore, restoration of PON2 in macrophages reduced lesional apoptosis and atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. Our data suggest that macrophage PON2 modulates mechanisms that link ER stress, mitochondrial dysfunction and the development of atherosclerosis.
ESTHER : Devarajan_2012_Mol.Genet.Metab_107_416
PubMedSearch : Devarajan_2012_Mol.Genet.Metab_107_416
PubMedID: 22864055

Title : Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer - Witte_2012_J.Lipids_2012_342806
Author(s) : Witte I , Foerstermann U , Devarajan A , Reddy ST , Horke S
Ref : J Lipids , 2012 :342806 , 2012
Abstract : Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer.
ESTHER : Witte_2012_J.Lipids_2012_342806
PubMedSearch : Witte_2012_J.Lipids_2012_342806
PubMedID: 22666600

Title : Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2\/apoE axis on the macrophage inflammatory response - Bourquard_2011_Biochem.J_436_91
Author(s) : Bourquard N , Ng CJ , Reddy ST
Ref : Biochemical Journal , 436 :91 , 2011
Abstract : Hepatic glucose metabolism is strongly influenced by oxidative stress and pro-inflammatory stimuli. PON2 (paraoxonase 2), an enzyme with undefined antioxidant properties, protects against atherosclerosis. PON2-deficient (PON2-def) mice have elevated hepatic oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages. In the present paper, we demonstrate that PON2 deficiency is associated with inhibitory insulin-mediated phosphorylation of hepatic IRS-1 (insulin receptor substrate-1). Unexpectedly, we observed a marked improvement in the hepatic IRS-1 phosphorylation state in PON2-def/apoE (apolipoprotein E)(-/-) mice, relative to apoE(-/-) mice. Factors secreted from activated macrophage cultures derived from PON2-def and PON2-def/apoE(-/-) mice are sufficient to modulate insulin signalling in cultured hepatocytes in a manner similar to that observed in vivo. We show that the protective effect on insulin signalling in PON2-def/apoE(-/-) mice is directly associated with altered production of macrophage pro-inflammatory mediators, but not elevated intracellular oxidative stress levels. We further present evidence that modulation of the macrophage inflammatory response in PON2-def/apoE(-/-) mice is mediated by a shift in the balance of NO and ONOO(-) (peroxynitrite) formation. Our results demonstrate that PON2 plays an important role in hepatic insulin signalling and underscores the influence of macrophage-mediated inflammatory response on hepatic insulin sensitivity.
ESTHER : Bourquard_2011_Biochem.J_436_91
PubMedSearch : Bourquard_2011_Biochem.J_436_91
PubMedID: 21361875

Title : Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis - Devarajan_2011_Antioxid.Redox.Signal_14_341
Author(s) : Devarajan A , Bourquard N , Hama S , Navab M , Grijalva VR , Morvardi S , Clarke CF , Vergnes L , Reue K , Teiber JF , Reddy ST
Ref : Antioxid Redox Signal , 14 :341 , 2011
Abstract : Increased production of reactive oxygen species (ROS) as a result of decreased activities of mitochondrial electron transport chain (ETC) complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. Our previous studies established that paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. The aim of the present study was to determine the mechanism by which PON2 modulates ROS production. In this report, we demonstrate that PON2-def mice on the hyperlipidemic apolipoprotein E(-/-) background (PON2-def/apolipoprotein E(-/-)) develop exacerbated atherosclerotic lesions with enhanced mitochondrial oxidative stress. We show that PON2 protein is localized to the inner mitochondrial membrane, where it is found associated with respiratory complex III. Employing surface-plasmon-resonance, we demonstrate that PON2 binds with high affinity to coenzyme Q(10), an important component of the ETC. Enhanced mitochondrial oxidative stress in PON2-def mice was accompanied by significantly reduced ETC complex I + III activities, oxygen consumption, and adenosine triphosphate levels in PON2-def mice. In contrast, overexpression of PON2 effectively protected mitochondria from antimycin- or oligomycin-mediated mitochondrial dysfunction. Our results illustrate that the antiatherogenic effects of PON2 are, in part, mediated by the role of PON2 in mitochondrial function.
ESTHER : Devarajan_2011_Antioxid.Redox.Signal_14_341
PubMedSearch : Devarajan_2011_Antioxid.Redox.Signal_14_341
PubMedID: 20578959

Title : Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule - Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
Author(s) : Kim JB , Xia YR , Romanoski CE , Lee S , Meng Y , Shi YS , Bourquard N , Gong KW , Port Z , Grijalva V , Reddy ST , Berliner JA , Lusis AJ , Shih DM
Ref : Arterioscler Thromb Vasc Biol , 31 :2624 , 2011
Abstract : OBJECTIVE: Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression. METHODS AND
RESULTS: Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC. CONCLUSION: 3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
ESTHER : Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
PubMedSearch : Kim_2011_Arterioscler.Thromb.Vasc.Biol_31_2624
PubMedID: 21836061

Title : Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function - Watson_2011_J.Lipid.Res_52_361
Author(s) : Watson CE , Weissbach N , Kjems L , Ayalasomayajula S , Zhang Y , Chang I , Navab M , Hama S , Hough G , Reddy ST , Soffer D , Rader DJ , Fogelman AM , Schecter A
Ref : J Lipid Res , 52 :361 , 2011
Abstract : L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.
ESTHER : Watson_2011_J.Lipid.Res_52_361
PubMedSearch : Watson_2011_J.Lipid.Res_52_361
PubMedID: 21068008

Title : Paraoxonase-1 and clopidogrel efficacy -
Author(s) : Camps J , Joven J , Mackness B , Mackness MI , Tawfik DS , Draganov DI , Costa LG , Paragh G , Seres I , Horke S , James RW , Hernandez AF , Reddy ST , Shih DM , Navab M , Rochu D , Aviram M
Ref : Nat Med , 17 :1041 , 2011
PubMedID: 21900915

Title : Putative innate immunity of antiatherogenic paraoxanase-2 via STAT5 signal transduction in HIV-1 infection of hematopoietic TF-1 cells and in SCID-hu mice - Yuan_2010_J.Stem.Cells_5_43
Author(s) : Yuan J , Devarajan A , Moya-Castro R , Zhang M , Evans S , Bourquard N , Dias P , Lacout C , Vainchenker W , Reddy ST , Koka PS
Ref : J Stem Cells , 5 :43 , 2010
Abstract : Paraoxanase-2 (PON2) activity was increased upon HIV-1 infection of the CD34+CD4+ hematopoietic cell line TF-1. Thymocytes derived from the human fetal conjoint thymus/liver hematopoietic organ of SCID-hu mice also exhibited an increase in PON2 activity. Additionally, a remarkable increase of PON2 mRNA expression was also observed in both TF-1 and thymocytes following HIV-1 infection. The phosphorylation of STAT5 was decreased in TF-1 cells upon HIV-1 infection. Interestingly, phosphorylation of STAT5 does not occur in GM-CSF "starved" TF-1 cells; however, PON2 protein, activity and mRNA expression are increased under these conditions, similar to HIV-1 infection. We conclude that PON2 is induced in HIV-1 infection through a mechanism that may involve STAT5 inactivation.
ESTHER : Yuan_2010_J.Stem.Cells_5_43
PubMedSearch : Yuan_2010_J.Stem.Cells_5_43
PubMedID: 20861927

Title : Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1 - Rosenblat_2009_J.Lipid.Res_50_870
Author(s) : Rosenblat M , Coleman R , Reddy ST , Aviram M
Ref : J Lipid Res , 50 :870 , 2009
Abstract : This study questioned the role of paraoxonase 2 (PON2) in attenuation of macrophage lipids accumulation. Mouse peritoneal macrophages (MPMs) harvested from PON2-deficient mice versus control C57BL/6 mice, look like foam cells and were larger in size and filled with lipid droplets. Macrophage triglyceride (but not cholesterol) content, biosynthesis rate, and microsomal acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) activity (not mRNA and protein) in PON2-deficient versus control MPM were all significantly increased by 4.6-, 3.6-, and 4.4-fold, respectively. Similarly, microsomal DGAT1 activity and cellular triglyceride content were significantly decreased in human PON2-transfected cells as well as upon incubation of PON2-deficient MPM with recombinant PON2. In all the above experimental systems, PON2 also decreased macrophage oxidative state. Incubation of PON2-deficient MPM with the free radicals generator 2,2'-amidinopropane hydrochloride increased cellular oxidative stress and DGAT1 activity by 2.2- and 3.4-fold, respectively, whereas incubation of microsomes from PON2-deficient MPM with superoxide dismutase decreased DGAT1 activity by 40%. We thus conclude that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state.
ESTHER : Rosenblat_2009_J.Lipid.Res_50_870
PubMedSearch : Rosenblat_2009_J.Lipid.Res_50_870
PubMedID: 19091699

Title : Is it just paraoxonase 1 or are other members of the paraoxonase gene family implicated in atherosclerosis? - Reddy_2008_Curr.Opin.Lipidol_19_405
Author(s) : Reddy ST , Devarajan A , Bourquard N , Shih DM , Fogelman AM
Ref : Curr Opin Lipidol , 19 :405 , 2008
Abstract : PURPOSE OF REVIEW: During the past decade, paraoxonase 1, a HDL-associated protein, has been demonstrated to be an important contributor to the antioxidant capacity of HDL. Studies using paraoxonase 1 null mice by gene targeting and transgenic mice corroborated the hypothesis that paraoxonase 1 protects against atherosclerosis. In contrast to paraoxonase 1, the other two members of the paraoxonase gene family, namely paraoxonase 2 and paraoxonase 3, are either undetectable (paraoxonase 2) or detected at very low levels (paraoxonase 3) on HDL, and are considered to participate in intracellular antioxidant mechanisms. In this review, we summarize studies reported in the past 2 years suggesting a protective role for paraoxonase 2 and paraoxonase 3 in the development of atherosclerosis in mice. RECENT FINDINGS: Adenovirus-mediated expression of human paraoxonase 2 or paraoxonase 3 proteins protects against the development of atherosclerosis in apolipoprotein E-deficient mice. Paraoxonase 2-deficient mice develop significantly larger atherosclerotic lesions than their wild-type and heterozygous counterparts on an atherogenic diet despite having lower levels of apolipoprotein B-containing lipoproteins. Atherosclerotic lesions were significantly lower in male hPON3Tg/LDLR null mice than in LDLR null mice on a western diet. SUMMARY: We conclude that, in addition to paraoxonase 1, both paraoxonase 2 and paraoxonase 3 proteins are protective against the development of atherosclerosis in mice. These findings underscore the utility of all members of the paraoxonase gene family as therapeutic targets for the treatment of atherosclerosis.
ESTHER : Reddy_2008_Curr.Opin.Lipidol_19_405
PubMedSearch : Reddy_2008_Curr.Opin.Lipidol_19_405
PubMedID: 18607188

Title : A novel anti-atherogenic role for COX-2--potential mechanism for the cardiovascular side effects of COX-2 inhibitors - Narasimha_2007_Prostaglandins.Other.Lipid.Mediat_84_24
Author(s) : Narasimha A , Watanabe J , Lin JA , Hama S , Langenbach R , Navab M , Fogelman AM , Reddy ST
Ref : Prostaglandins Other Lipid Mediat , 84 :24 , 2007
Abstract : Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by lipid accumulation, lipoprotein oxidation, and inflammation. Products of the cyclooxygenase (COX) pathway participate in acute and chronic inflammation. The inducible form of COX, COX-2, generates lipid mediators of inflammation that are pro-inflammatory and COX-2-selective inhibitors are potent anti-inflammatory agents. However, clinical data suggest an increased risk of cardiovascular side effects in patients using COX-2-selective inhibitors. In this paper, we sought to determine the effect of COX-2 deficiency on atherosclerosis-related lipoprotein metabolism in mice. We demonstrate that COX-2 deficiency resulted in (i) accumulation of lipids in circulation and liver, (ii) pro-inflammatory properties of HDL as measured by HDL's increased reactive oxygen species (ROS) content, decreased paraoxonase 1 (PON1) activity, decreased serum apoA-1, reduced ability to efflux cholesterol and to prevent LDL oxidizability, and (iii) increased TXB(2) in circulation. Moreover, when placed on an atherogenic diet, COX-2 deficiency resulted in (i) increased lipid deposition in the aorta, (ii) a further dramatic imbalance in circulating eicosanoids, i.e. decreased serum PGI(2) coupled with increased PGE(2) and TXB(2), and (iii) a marked elevation of pro-inflammatory cytokines, TNF and IL-6. Our results suggest, for the first time, that COX-2 deficiency contributes to the pro-atherogenic properties of HDL in mice.
ESTHER : Narasimha_2007_Prostaglandins.Other.Lipid.Mediat_84_24
PubMedSearch : Narasimha_2007_Prostaglandins.Other.Lipid.Mediat_84_24
PubMedID: 17643885

Title : Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice - Shih_2007_Circ.Res_100_1200
Author(s) : Shih DM , Xia YR , Wang XP , Wang SS , Bourquard N , Fogelman AM , Lusis AJ , Reddy ST
Ref : Circulation Research , 100 :1200 , 2007
Abstract : Paraoxonase 3 (PON3) is a member of the PON family, which includes PON1, PON2, and PON3. Recently, PON3 was shown to prevent the oxidation of low-density lipoprotein in vitro. To test the role of PON3 in atherosclerosis and related traits, 2 independent lines of human PON3 transgenic (Tg) mice on the C57BL/6J (B6) background were constructed. Human PON3 mRNA was detected in various tissues, including liver, lung, kidney, brain, adipose, and aorta, of both lines of Tg mice. The human PON3 mRNA levels in the livers of PON3 Tg mice were 4- to 7-fold higher as compared with the endogenous mouse Pon3 mRNA levels. Human PON3 protein and activity were detected in the livers of Tg mice as well. No significant differences in plasma total, high-density lipoprotein, and very-low-density lipoprotein/low-density lipoprotein cholesterol and triglyceride and glucose levels were observed between the PON3 Tg and non-Tg mice. Interestingly, atherosclerotic lesion areas were significantly smaller in both lines of male PON3 Tg mice as compared with the male non-Tg littermates on B6 background fed an atherogenic diet. When bred onto the low-density lipoprotein receptor knockout mouse background, the male PON3 Tg mice also exhibited decreased atherosclerotic lesion areas and decreased expression of monocyte chemoattractant protein-1 in the aorta as compared with the male non-Tg littermates. In addition, decreased adiposity and lower circulating leptin levels were observed in both lines of male PON3 Tg mice as compared with the male non-Tg mice. In an F2 cross, adipose Pon3 mRNA levels inversely correlated with adiposity and related traits. Our study demonstrates that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adiposity in male mice. PON3 may play an important role in protection against obesity and atherosclerosis.
ESTHER : Shih_2007_Circ.Res_100_1200
PubMedSearch : Shih_2007_Circ.Res_100_1200
PubMedID: 17379834

Title : Adenovirus-mediated expression of human paraoxonase 3 protects against the progression of atherosclerosis in apolipoprotein E-deficient mice - Ng_2007_Arterioscler.Thromb.Vasc.Biol_27_1368
Author(s) : Ng CJ , Bourquard N , Hama SY , Shih DM , Grijalva VR , Navab M , Fogelman AM , Reddy ST
Ref : Arterioscler Thromb Vasc Biol , 27 :1368 , 2007
Abstract : OBJECTIVE: We have previously reported that human paraoxonase 3 (PON3) is an HDL-associated protein capable of preventing LDL oxidation in vitro. The objective of the present study was to determine whether elevated levels of human PON3 in mice could protect against the progression of atherosclerosis in vivo. METHODS AND
RESULTS: Twenty-six week-old apolipoprotein E-deficient mice were injected with 3x10(11) particles of adenovirus expressing either GFP alone (AdGFP) or together with human PON3 (AdPON3). Three weeks after injection, lesion area was significantly lower in AdPON3-treated mice compared with AdGFP controls. Serum from AdPON3 mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL was less susceptible to oxidation, whereas HDL was more capable of protecting against LDL oxidation. Exogenous human PON3 was not detected in the serum or HDL and more surprisingly we demonstrate that endogenous mouse PON3 is not associated with HDL, suggesting that the antioxidant function of PON3 is at the cellular level in mice.
CONCLUSIONS: This study demonstrates for the first time that PON3 enhances the antiatherogenic capacity of serum and protects against the progression of atherosclerosis in vivo.
ESTHER : Ng_2007_Arterioscler.Thromb.Vasc.Biol_27_1368
PubMedSearch : Ng_2007_Arterioscler.Thromb.Vasc.Biol_27_1368
PubMedID: 17446441

Title : Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia - Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
Author(s) : Stoltz DA , Ozer EA , Ng CJ , Yu JM , Reddy ST , Lusis AJ , Bourquard N , Parsek MR , Zabner J , Shih DM
Ref : American Journal of Physiology Lung Cell Mol Physiol , 292 :L852 , 2007
Abstract : Pseudomonas aeruginosa is an important cause of nosocomial infections and is frequently present in the airways of cystic fibrosis patients. Quorum sensing mediates P. aeruginosa's virulence and biofilm formation through density-dependent interbacterial signaling with autoinducers. N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is the major autoinducer in P. aeruginosa. We have previously shown that human airway epithelia and paraoxonases (PONs) degrade 3OC12-HSL. This study investigated the role of PON1, PON2, and PON3 in airway epithelial cell inactivation of 3OC12-HSL. All three PONs were present in murine tracheal epithelial cells, with PON2 and PON3 expressed at the highest levels. Lysates of tracheal epithelial cells from PON2, but not PON1 or PON3, knockout mice had impaired 3OC12-HSL inactivation compared with wild-type mice. In contrast, PON1-, PON2-, or PON3-targeted deletions did not affect 3OC12-HSL degradation by intact epithelia. Overexpression of PON2 enhanced 3OC12-HSL degradation by human airway epithelial cell lysates but not by intact epithelia. Finally, using a quorum-sensing reporter strain of P. aeruginosa, we found that quorum sensing was enhanced in PON2-deficient airway epithelia. In summary, these results show that loss of PON2 impairs 3OC12-HSL degradation by airway epithelial cells and suggests that diffusion of 3OC12-HSL into the airway cells can be the rate-limiting step for degradation of the molecule.
ESTHER : Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
PubMedSearch : Stoltz_2007_Am.J.Physiol.Lung.Cell.Mol.Physiol_292_L852
PubMedID: 17122353

Title : Mechanisms of disease: proatherogenic HDL--an evolving field - Navab_2006_Nat.Clin.Pract.Endocrinol.Metab_2_504
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Van Lenten BJ , Ansell BJ , Fogelman AM
Ref : Nat Clin Pract Endocrinol Metab , 2 :504 , 2006
Abstract : It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.
ESTHER : Navab_2006_Nat.Clin.Pract.Endocrinol.Metab_2_504
PubMedSearch : Navab_2006_Nat.Clin.Pract.Endocrinol.Metab_2_504
PubMedID: 16957764

Title : Potential clinical utility of high-density lipoprotein-mimetic peptides - Navab_2006_Curr.Opin.Lipidol_17_440
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Van Lenten BJ , Datta G , Garber D , Fogelman AM
Ref : Curr Opin Lipidol , 17 :440 , 2006
Abstract : PURPOSE OF REVIEW: To determine the potential clinical utility of high-density lipoprotein-mimetic peptides. RECENT FINDINGS: Oral administration of D-4F together with pravastatin caused lesion regression in old apoE null mice. Administration of D-4F to low-density lipoprotein receptor null mice fed a Western diet reduced the association of myeloperoxidase with apoA-I and reduced the 3-nitrotyrosine content of apoA-I. Oral D-4F improved arterial vasoreactivity independent of apoA-I. Mice genetically lacking apoA-I showed significant improvement in vasoreactivity but, in contrast to mice with apoA-I, did not demonstrate reduced arterial wall thickness after D-4F treatment. In a rat model of diabetes, D-4F administration induced heme oxygenase-1 and extracellular superoxide dismutase, prevented endothelial sloughing, and dramatically improved arterial vasoreactivity. A peptide with 10 D-amino acid residues taken from the sequence of apoJ rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and dramatically reduced atherosclerosis in apoE null mice. Oral administration of tetrapeptides synthesized from either L-amino acids or D-amino acids rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and reduced atherosclerosis in apoE null mice. SUMMARY: Peptides that sequester lipoprotein lipid hydroperoxides release a series of high-density lipoprotein-associated antioxidant enzymes such as paraoxonase from inhibition and protect apoA-I from oxidative damage that would impair cholesterol efflux.
ESTHER : Navab_2006_Curr.Opin.Lipidol_17_440
PubMedSearch : Navab_2006_Curr.Opin.Lipidol_17_440
PubMedID: 16832169

Title : Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2 - Ng_2006_J.Biol.Chem_281_29491
Author(s) : Ng CJ , Bourquard N , Grijalva V , Hama S , Shih DM , Navab M , Fogelman AM , Lusis AJ , Young S , Reddy ST
Ref : Journal of Biological Chemistry , 281 :29491 , 2006
Abstract : Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (-32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.
ESTHER : Ng_2006_J.Biol.Chem_281_29491
PubMedSearch : Ng_2006_J.Biol.Chem_281_29491
PubMedID: 16891303

Title : Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice - Ng_2006_Mol.Genet.Metab_89_368
Author(s) : Ng CJ , Hama SY , Bourquard N , Navab M , Reddy ST
Ref : Mol Genet Metab , 89 :368 , 2006
Abstract : Accumulating evidence suggests that the oxidative modification of low-density lipoprotein (LDL) plays an integral role in the initiation and progression of atherosclerosis. We have previously reported that human paraoxonase (PON)2 possesses antioxidant properties and is capable of preventing LDL oxidation in vitro. The objective of this study was to determine whether elevated levels of PON2 could protect against the development of atherosclerosis in vivo. Six-month-old apolipoprotein E-deficient mice (apoE(-/-)) were injected intravenously with either PBS or 3 x 10(11) particles of adenovirus expressing GFP (AdGFP) or human PON2 (AdPON2). Three weeks post-injection, lesion area was significantly lower in mice treated with AdPON2 compared to their control counterparts. Serum from AdPON2 treated mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL from AdPON2 treated mice was less susceptible to oxidation, while HDL from these same mice was significantly more capable of protecting LDL against oxidation. These results demonstrate for the first time that elevated levels of PON2 can enhance the efflux potential and antioxidant capacity of serum, increase the anti-inflammatory properties of HDL, and protect against the development of atherosclerosis in vivo.
ESTHER : Ng_2006_Mol.Genet.Metab_89_368
PubMedSearch : Ng_2006_Mol.Genet.Metab_89_368
PubMedID: 16935014

Title : Oral amphipathic peptides as therapeutic agents - Reddy_2006_Expert.Opin.Investig.Drugs_15_13
Author(s) : Reddy ST , Anantharamaiah GM , Navab M , Hama S , Hough G , Grijalva V , Garber DW , Datta G , Fogelman AM
Ref : Expert Opin Investig Drugs , 15 :13 , 2006
Abstract : Cholesterol can promote inflammation by its ability to stimulate the production of reactive oxygen species that result in the formation of pro-inflammatory oxidised phospholipids. High-density lipoproteins (HDLs) are part of the innate immune response and can be either pro- or anti-inflammatory independently of plasma HDL-cholesterol levels. During systemic inflammation as occurs with atherosclerosis, Apolipoprotein A-I can be altered, reducing its ability to promote reverse cholesterol transport and HDL can become pro-inflammatory. Amphipathic peptides with either a class A amphipathic helix (D-4F) or a class G* amphipathic helix (D-[113-122]apoJ), or even those that are too small to form a helix (KRES and FREL) have some similar characteristics. Their interaction with lipids leads to a reduction in lipoprotein-lipid hydroperoxides that releases HDL-associated antioxidant enzymes, such as paraoxonase, therefore providing antiatherosclerosis and anti-inflammatory activity. In addition, the peptide D-4F stimulates the formation and cycling of pre-beta HDL. These amphipathic peptides appear to have therapeutic potential as oral agents.
ESTHER : Reddy_2006_Expert.Opin.Investig.Drugs_15_13
PubMedSearch : Reddy_2006_Expert.Opin.Investig.Drugs_15_13
PubMedID: 16370930

Title : Understanding changes in high density lipoproteins during the acute phase response -
Author(s) : Van Lenten BJ , Reddy ST , Navab M , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 26 :1687 , 2006
PubMedID: 16857958

Title : D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice - Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1426
Author(s) : Navab M , Anantharamaiah GM , Hama S , Hough G , Reddy ST , Frank JS , Garber DW , Handattu S , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 25 :1426 , 2005
Abstract : OBJECTIVE: We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents. METHODS AND
RESULTS: The combination significantly increased high-density lipoprotein (HDL)-cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area; P<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (P=0.019 for en face lesion area; P=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone; P<0.00004) with a 22% reduction in macrophage content in the remaining lesions (P=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (P=0.011). In monkeys, the combination also rendered HDL antiinflammatory.
CONCLUSIONS: These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.
ESTHER : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1426
PubMedSearch : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1426
PubMedID: 15845909

Title : Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in ApoE null mice - Navab_2005_Circ.Res_97_524
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Hama S , Hough G , Frank JS , Grijalva VR , Ganesh VK , Mishra VK , Palgunachari MN , Fogelman AM
Ref : Circulation Research , 97 :524 , 2005
Abstract : A peptide containing only 4 amino acid residues (KRES) that is too small to form an amphipathic helix, reduced lipoprotein lipid hydroperoxides (LOOH), increased paraoxonase activity, increased plasma HDL-cholesterol levels, rendered HDL antiinflammatory, and reduced atherosclerosis in apoE null mice. KRES was orally effective when synthesized from either L or D-amino acids suggesting that peptide-protein interactions were not required. Remarkably, changing the order of 2 amino acids (from KRES to KERS) resulted in the loss of all biologic activity. Solubility in ethyl acetate and interaction with lipids, as determined by differential scanning calorimetry, indicated significant differences between KRES and KERS. Negative stain electron microscopy showed that KRES formed organized peptide-lipid structures whereas KERS did not. Another tetrapeptide FREL shared many of the physical-chemical properties of KRES and was biologically active in mice and monkeys when synthesized from either L- or D-amino acids. After oral administration KRES and FREL were found associated with HDL whereas KERS was not. We conclude that the ability of peptides to interact with lipids, remove LOOH and activate antioxidant enzymes associated with HDL determines their antiinflammatory and antiatherogenic properties regardless of their ability to form amphipathic helixes.
ESTHER : Navab_2005_Circ.Res_97_524
PubMedSearch : Navab_2005_Circ.Res_97_524
PubMedID: 16100046

Title : Apolipoprotein A-I mimetic peptides - Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1325
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Hama S , Hough G , Grijalva VR , Yu N , Ansell BJ , Datta G , Garber DW , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 25 :1325 , 2005
Abstract : Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-beta HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.
ESTHER : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1325
PubMedSearch : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1325
PubMedID: 15831812

Title : An oral apoJ peptide renders HDL antiinflammatory in mice and monkeys and dramatically reduces atherosclerosis in apolipoprotein E-null mice - Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1932
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Van Lenten BJ , Wagner AC , Hama S , Hough G , Bachini E , Garber DW , Mishra VK , Palgunachari MN , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 25 :1932 , 2005
Abstract : OBJECTIVE: To determine the properties of a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein (apo) J. METHODS AND
RESULTS: In contrast to D-4F, D- [113-122]apoJ showed minimal self-association and helicity in the absence of lipids. D-4F increased the concentration of apoA-I with pre-beta mobility in apoE-null mice whereas D- [113-122]apoJ did not. After an oral dose D- [113-122]apoJ more slowly associated with lipoproteins and was cleared from plasma much more slowly than D-4F. D- [113-122]apoJ significantly improved the ability of plasma to promote cholesterol efflux and improved high-density lipoprotein (HDL) inflammatory properties for up to 48 hours after a single oral dose in apoE-null mice, whereas scrambled D- [113-122]apoJ did not. Oral administration of 125 microg/mouse/d of D- [113-122]apoJ reduced atherosclerosis in apoE-null mice (70.2% reduction in aortic root sinus lesion area, P=4.3 x 10(-13); 70.5% reduction by en face analysis, P=1.5 x 10(-6)). In monkeys, oral D- [113-122]apoJ rapidly reduced lipoprotein lipid hydroperoxides (LOOH) and improved HDL inflammatory properties. Adding 250 ng/mL of D-[113-122]apoJ (but not scrambled D- [113-122]apoJ) to plasma in vitro reduced LOOH and increased paraoxonase activity.
CONCLUSIONS: Oral D- [113-122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.
ESTHER : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1932
PubMedSearch : Navab_2005_Arterioscler.Thromb.Vasc.Biol_25_1932
PubMedID: 15961700

Title : The paraoxonase gene family and atherosclerosis - Ng_2005_Free.Radic.Biol.Med_38_153
Author(s) : Ng CJ , Shih DM , Hama SY , Villa N , Navab M , Reddy ST
Ref : Free Radic Biol Med , 38 :153 , 2005
Abstract : Epidemiologic, genetic, and biochemical studies support an antiatherogenic role for paraoxonase (PON) 1. While the precise mechanism by which PON1 protects against the development of atherosclerosis is unclear, in vitro studies and the results from PON1 knockout and transgenic mice suggest that this protective effect may be attributed to PON1's ability to attenuate the oxidative modification of lipoprotein particles. The two other members of the PON gene family, namely, PON2 and PON3, have also been reported to possess antioxidant properties and may exhibit antiatherogenic capacities as well. Previous studies have demonstrated that PON1 expression is downregulated by oxidative stress. In contrast, more recent studies have shown that PON2 expression is upregulated in response to oxidative stress-inducing agents, while PON3 expression remains unchanged. While the physiological function of these proteins is unknown, studies currently underway using PON2 and PON3 knockout and transgenic mice should enable us to tease out the apparently redundant functions of these three proteins and yield clues as to their physiological function as well as their role in atherogenesis.
ESTHER : Ng_2005_Free.Radic.Biol.Med_38_153
PubMedSearch : Ng_2005_Free.Radic.Biol.Med_38_153
PubMedID: 15607899

Title : Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice - Navab_2004_Circulation_109_3215
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Hama S , Hough G , Grijalva VR , Wagner AC , Frank JS , Datta G , Garber D , Fogelman AM
Ref : Circulation , 109 :3215 , 2004
Abstract : BACKGROUND: These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice. METHODS AND
RESULTS: Twenty minutes after 500 microg of D-4F was given orally to apoE-null mice, small cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-beta mobility and enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F, both mature HDL and the fast protein liquid chromatography fractions containing the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs became antiinflammatory, and there was an increase in HDL-mediated cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages in vivo. In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides (LOOH), except for pre-beta HDL fractions, in which LOOH increased.
CONCLUSIONS: The mechanism of action of oral D-4F in apoE-null mice involves rapid formation of CCPs, with pre-beta mobility enriched in apoA-I and paraoxonase activity. As a result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL-mediated cholesterol efflux and reverse cholesterol transport from macrophages are stimulated.
ESTHER : Navab_2004_Circulation_109_3215
PubMedSearch : Navab_2004_Circulation_109_3215
PubMedID: 15197147

Title : Human apolipoprotein A-I and A-I mimetic peptides: potential for atherosclerosis reversal - Navab_2004_Curr.Opin.Lipidol_15_645
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Van Lenten BJ , Datta G , Garber D , Fogelman AM
Ref : Curr Opin Lipidol , 15 :645 , 2004
Abstract : PURPOSE OF REVIEW: Recent publications related to the potential use of apolipoprotein (apo)A-I and apoA-I mimetic peptides in the treatment of atherosclerosis are reviewed. RECENT FINDINGS: A preliminary report indicating that infusion of apoA-IMilano into humans once weekly for 5 weeks caused a significant decrease in coronary artery atheroma volume has sparked great interest in the potential therapeutic use of apoA-I. Recent studies have revealed that HDL quality (e.g. HDL apolipoprotein and lipid content, including oxidized lipids, particle size and electrophoretic mobility, associated enzymatic activities, inflammatory/anti-inflammatory properties, and ability to promote cholesterol efflux) may be more important than HDL-cholesterol levels. Therefore, when developing new strategies to raise HDL-cholesterol concentrations by interfering with HDL metabolism, one must consider the quality of the resulting HDL. In animal models, raising HDL-cholesterol levels by administering oral phospholipids improved both the quantity and quality of HDL and was associated with lesion regression. An apoA-I mimetic peptide, namely 4F synthesized from D-amino acids (D-4F), administered orally to mice did not raise HDL-cholesterol concentrations but promoted the formation of pre-beta HDL containing increased paraoxonase activity, resulting in significant improvements in HDL's anti-inflammatory properties and ability to promote cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol efflux from macrophages in vivo. SUMMARY: The quality of HDL may be more important than HDL-cholesterol levels. ApoA-I and apoA-I mimetic peptides appear to have significant therapeutic potential in atherosclerosis.
ESTHER : Navab_2004_Curr.Opin.Lipidol_15_645
PubMedSearch : Navab_2004_Curr.Opin.Lipidol_15_645
PubMedID: 15529023

Title : Apparent paradox of low-fat healthy diets increasing plasma levels of oxidized low-density lipoprotein and lipoprotein(a) -
Author(s) : Navab M , Reddy ST , Van Lenten BJ , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 24 :392 , 2004
PubMedID: 15003971

Title : Human apolipoprotein AI mimetic peptides for the treatment of atherosclerosis - Navab_2003_Curr.Opin.Investig.Drugs_4_1100
Author(s) : Navab M , Anantharamaiah GM , Reddy ST , Van Lenten BJ , Hough G , Wagner A , Nakamura K , Garber DW , Datta G , Segrest JP , Hama S , Fogelman AM
Ref : Curr Opin Investig Drugs , 4 :1100 , 2003
Abstract : The effects of apolipoprotein (Apo) AI mimetic peptide synthesized from D- and L-amino acids on atherosclerotic lesion formation were investigated in low-density lipoprotein (LDL) receptor-deficient mice on a Western diet and in apoE null mice. In addition, their effects on the inflammatory changes induced in LDL-receptor mice fed a Western diet following influenza A infection were studied. When apolipoprotein AI mimetic peptides synthesized from either D- or L-amino acids were administered to LDL-receptor null mice, only peptides synthesized from D-amino acids were stable in the circulation and enhanced the ability of high-density lipoprotein (HDL) to protect LDL against oxidation. Administration of the peptide D-4F to LDL-receptor null mice and apoE null mice decreased lesion size. Additionally, in LDL receptor null mice after influenza infection, D-4F treatment increased plasma HDL levels and paraoxonase activity, and inhibited increased in LDL-cholesterol and peak levels of interleukin-6 post-infection. Injection of female mice with male macrophages, and subsequent measurement of the male 'sry' gene, revealed a marked increase in macrophage traffic into the aortic arch after infection that was prevented by administration of D-4F. This indicates that: (i) oral D-4F has powerful anti-atherosclerotic properties, and (ii) the loss of the anti-inflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.
ESTHER : Navab_2003_Curr.Opin.Investig.Drugs_4_1100
PubMedSearch : Navab_2003_Curr.Opin.Investig.Drugs_4_1100
PubMedID: 14582455

Title : Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein - Ng_2001_J.Biol.Chem_276_44444
Author(s) : Ng CJ , Wadleigh DJ , Gangopadhyay A , Hama S , Grijalva VR , Navab M , Fogelman AM , Reddy ST
Ref : Journal of Biological Chemistry , 276 :44444 , 2001
Abstract : The oxidation of apolipoprotein B-containing lipoproteins and cell membrane lipids is believed to play an integral role in the development of fatty streak lesions, an initial step in atherogenesis. We have previously shown that two antioxidant-like enzymes, paraoxonase (PON)-1 and PON3, are high density lipoprotein-associated proteins capable of preventing the oxidative modification of low density lipoprotein (LDL) (Reddy, S. T., Wadleigh, D. J., Grijalva, V., Ng, C., Hama, S., Gangopadhyay, A., Shih, D. M., Lusis, A. J., Navab, M., and Fogelman, A. M. (2001) Arterioscler. Thromb. Vasc. Biol. 21, 542-547). In the present study, we demonstrate that PON2 (i) is not associated with high density lipoprotein; (ii) has antioxidant properties; and (iii) prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL (MM-LDL), and inhibits the ability of MM-LDL to induce monocyte chemotaxis. The PON2 protein was overexpressed in HeLa cells using the tetracycline-inducible ("Tet-On") system, and its antioxidant capacity was measured in a fluorometric assay. Cells that overexpressed PON2 showed significantly less intracellular oxidative stress following treatment with hydrogen peroxide or oxidized phospholipid. Moreover, cells that overexpressed PON2 were also less effective in oxidizing and modifying LDL and, in fact, were able to reverse the effects of preformed MM-LDL. Our results suggest that PON2 possesses antioxidant properties similar to those of PON1 and PON3. However, in contrast to PON1 and PON3, PON2 may exert its antioxidant functions at the cellular level, joining the host of intracellular antioxidant enzymes that protect cells from oxidative stress.
ESTHER : Ng_2001_J.Biol.Chem_276_44444
PubMedSearch : Ng_2001_J.Biol.Chem_276_44444
PubMedID: 11579088

Title : Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids - Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
Author(s) : Reddy ST , Wadleigh DJ , Grijalva V , Ng C , Hama S , Gangopadhyay A , Shih DM , Lusis AJ , Navab M , Fogelman AM
Ref : Arterioscler Thromb Vasc Biol , 21 :542 , 2001
Abstract : Paraoxonase-1 (PON1) is a secreted protein associated primarily with high density lipoprotein (HDL) and participates in the prevention of low density lipoprotein (LDL) oxidation. Two other paraoxonase (PON) family members, namely, PON2 and PON3, have been identified. In this study, we report the cloning and characterization of the human PON3 gene from HepG2 cells. Tissue Northern analysis identifies an approximately 1.3-kb transcript for PON3 primarily in the liver. PON3-specific peptide antibodies detect an approximately 40-kDa protein associated with HDL and absent from LDL. Pretreatment of cultured human aortic endothelial cells with supernatants from HeLa Tet On cell lines overexpressing PON3 prevents the formation of mildly oxidized LDL and inactivates preformed mildly oxidized LDL. In contrast to PON1, PON3 is not active against the synthetic substrates paraoxon and phenylacetate. Furthermore, PON3 expression is not regulated in HepG2 cells by oxidized phospholipids and is not regulated in the livers of mice fed a high-fat atherogenic diet.
ESTHER : Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
PubMedSearch : Reddy_2001_Arterioscler.Thromb.Vasc.Biol_21_542
PubMedID: 11304470

Title : Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3 - Navab_2000_J.Lipid.Res_41_1495
Author(s) : Navab M , Hama SY , Anantharamaiah GM , Hassan K , Hough GP , Watson AD , Reddy ST , Sevanian A , Fonarow GC , Fogelman AM
Ref : J Lipid Res , 41 :1495 , 2000
Abstract : Treatment of human artery wall cells with apolipoprotein A-I (apoA-I), but not apoA-II, with an apoA-I peptide mimetic, or with high density lipoprotein (HDL), or paraoxonase, rendered the cells unable to oxidize low density lipoprotein (LDL). Human aortic wall cells were found to contain 12-lipoxygenase (12-LO) protein. Transfection of the cells with antisense to 12-LO (but not sense) eliminated the 12-LO protein and prevented LDL-induced monocyte chemotactic activity. Addition of 13(S)-hydroperoxyoctadecadienoic acid [13(S)-HPODE] and 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] dramatically enhanced the nonenzymatic oxidation of both 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and cholesteryl linoleate. On a molar basis 13(S)-HPODE and 15(S)-HPETE were approximately two orders of magnitude greater in potency than hydrogen peroxide in causing the formation of biologically active oxidized phospholipids (m/z 594, 610, and 828) from PAPC. Purified paraoxonase inhibited the biologic activity of these oxidized phospholipids. HDL from 10 of 10 normolipidemic patients with coronary artery disease, who were neither diabetic nor receiving hypolipidemic medications, failed to inhibit LDL oxidation by artery wall cells and failed to inhibit the biologic activity of oxidized PAPC, whereas HDL from 10 of 10 age- and sex-matched control subjects did. We conclude that a) mildly oxidized LDL is formed in three steps, one of which involves 12-LO and each of which can be inhibited by normal HDL, and b) HDL from at least some coronary artery disease patients with normal blood lipid levels is defective both in its ability to prevent LDL oxidation by artery wall cells and in its ability to inhibit the biologic activity of oxidized PAPC.
ESTHER : Navab_2000_J.Lipid.Res_41_1495
PubMedSearch : Navab_2000_J.Lipid.Res_41_1495
PubMedID: 10974057