Walker MC

References (2)

Title : Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development - Wilensky_2008_Nat.Med_14_1059
Author(s) : Wilensky RL , Shi Y , Mohler ER, 3rd , Hamamdzic D , Burgert ME , Li J , Postle A , Fenning RS , Bollinger JG , Hoffman BE , Pelchovitz DJ , Yang J , Mirabile RC , Webb CL , Zhang L , Zhang P , Gelb MH , Walker MC , Zalewski A , Macphee CH
Ref : Nat Med , 14 :1059 , 2008
Abstract : Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
ESTHER : Wilensky_2008_Nat.Med_14_1059
PubMedSearch : Wilensky_2008_Nat.Med_14_1059
PubMedID: 18806801
Gene_locus related to this paper: human-PLA2G7

Title : Cholinergic axons modulate GABAergic signaling among hippocampal interneurons via postsynaptic alpha 7 nicotinic receptors - Wanaverbecq_2007_J.Neurosci_27_5683
Author(s) : Wanaverbecq N , Semyanov A , Pavlov I , Walker MC , Kullmann DM
Ref : Journal of Neuroscience , 27 :5683 , 2007
Abstract : Homopentameric alpha7 nicotinic receptors have a high affinity for acetylcholine (ACh), are permeable to Ca2+ ions, and are abundant in hippocampal interneurons. Although nicotinic agonists evoke inward currents and Ca2+ transients in stratum radiatum interneurons, the role of endogenous ACh in modulating synaptic integration by interneurons is incompletely understood. Many cholinergic axonal varicosities do not have postsynaptic specializations, but alpha7 receptors frequently occur close to synaptic GABA(A) receptors. These observations raise the possibility that alpha7 nicotinic receptors activated by ACh released from cholinergic axons modulate GABAergic transmission in interneurons. We show that agonists of alpha7 receptors profoundly depress GABAergic IPSCs recorded in stratum radiatum interneurons in the CA1 region of the hippocampus. This depression is accompanied by a small increase in GABA release. Alpha7 nicotinic receptor agonists also depress GABA- or muscimol-evoked currents in interneurons, indicating that the major effect is a postsynaptic modulation of GABA(A) receptors. The depression of GABA-evoked currents is abolished by chelating Ca2+ in the recorded interneuron and attenuated by inhibitors of PKC. We also show that stimuli designed to release endogenous ACh from cholinergic axons evoke an alpha7 receptor-dependent heterosynaptic depression of GABAergic IPSCs in interneurons. This heterosynaptic modulation is amplified by blocking cholinesterases. These results reveal a novel mechanism by which cholinergic neurons modulate information processing in the hippocampus.
ESTHER : Wanaverbecq_2007_J.Neurosci_27_5683
PubMedSearch : Wanaverbecq_2007_J.Neurosci_27_5683
PubMedID: 17522313