Shear Stress-Induced Atherosclerotic Plaque Regression Explained By Increased Macrophage Efferocytosis And Migration

s S113 BACKGROUND: Atherosclerosis is a major underlying cause of cardiovascular disease; however, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. Recent evidence from our laboratory suggests that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3a/b is involved in the activation of pro-atherosclerotic processes. The objective of this study is to examine the effects of small molecules that interfere with ER stress-GSK3a/b signaling on the progression and regression of atherosclerosis in a mouse model system. METHODS AND RESULTS: To examine atherosclerotic progression, 5 week old female low density lipoprotein receptor deficient (LDLR) mice were placed on a high fat diet (HFD) for 15 weeks. Subsets of HFD fed mice were supplemented with a chemical chaperone (1g 4-phenylbutyric acid (PBA)/L drinking water) to attenuate ER stress, or a GSK3a/b inhibitor (625mg valproate (VPA)/kg body weight/day) (n1⁄48/ treatment group). At 20 weeks of age, all mice were sacrificed, ER stress levels and GSK3a/b activity was examined, and atherosclerosis was quantified in the aortic sinus. The results show that both PBAand VPA-supplemented mice have significantly reduced lesion areas and volumes (P<0.05). To examine potential effects on atherosclerotic regression, 5 week old LDLR mice were placed on a high fat diet (HFD) for 15 weeks. Subsets of mice were harvested at this time or switched to a chow (low fat) diet, or a chow diet supplemented with PBA or VPA for 4 weeks, as described above. All mice were analyzed for ER stress levels and GSK3a/b activity, and atherosclerosis was quantified in the aortic sinus. The results of this experiment indicate that the growth of the atherosclerotic lesion was arrested in mice switched to a regular chow diet at 20 weeks of age. Mice switched to chow diet supplemented with either PBA or VPA had reduced lesion areas and volumes. CONCLUSIONS: Pharmacological attenuation of ER stress or inhibition of GSK3a/b impedes the development of atherosclerosis in LDLR-/mice and appears to promote the regression of existing lesions. Together these data support the importance of ER stress-GSK3a/b signaling in atherogenesis. Trainee Research Award Finalist e Basic Science 215 SHEAR STRESS-INDUCED ATHEROSCLEROTIC PLAQUE REGRESSION EXPLAINED BY INCREASED MACROPHAGE EFFEROCYTOSIS & MIGRATION S Simeone, T Ebrahimian, V Michaud, S Lehoux