Rosenblat_2013_Atherosclerosis_226_110

OBJECTIVE: To assess the anti-atherogenic effects on macrophage cholesterol biosynthesis rate, and on cellular oxidative stress by the combination of simvastatin with a potent polyphenolic antioxidant (punicalagin), or with a phytosterol (beta-sitosterol), or with pomegranate juice (POM, that contains both of them). METHODS AND
RESULTS: Simvastatin (15 mug/ml) decreased J774A.1 macrophage cholesterol biosynthesis rate by 42% as compared to control cells. The addition to the statin of either punicalagin (15 or 30 muM), or beta-sitosterol (50 or 100 muM), increased the inhibitory effect of the statin up to 62% or 57%, respectively. Similarly, the combination of POM and simvastatin, resulted in an inhibitory effect up to 59%. While simvastatin inhibited the rate limiting enzyme HMGCoA-reductase, punicalagin, beta-sitosterol or POM inhibited macrophage cholesterol biosynthesis downstream to mevalonate. Simvastatin (15 mug/ml) also modestly decreased macrophage reactive oxygen species (ROS) formation by 11%. In the presence of punicalagin (15 or 30 muM) however, a remarkable further inhibition was noted (by 61% or 79%, respectively). Although beta-sitosterol alone showed some pro-oxidant activity, the combination of simvastatin, beta-sitosterol and punicalagin, clearly demonstrated a remarkable 73% reduction in ROS production. Similarly, simvastatin + POM decreased the extent of ROS formation by up to 63%. These improved antioxidant effects of the combinations could be related to various anti-oxidative properties of the different compounds, including free radicals scavenging capacity, upregulation of paraoxonase 2, and stimulation of reduced glutathione. CONCLUSION: The combination of simvastatin with potent antioxidant and phytosterol (such as present in pomegranate) could lead to attenuation of macrophage foam cell formation and atherogenesis.