Molecular Mechanisms and Treatment Strategies for Obesity-Associated Coronary Artery Disease, an Imminent Military Epidemic

摘要

There is an epidemic of obesity in the military. Obesity leads to type 2 diabetes, the most dangerous consequence of which is atherothrombotic vascular disease. Over the 4-year grant period, we have made major progress on the Key Tasks. We have gained more in-depth understanding on how CaMKII, NADPH oxidase, and IP3Rs - all AngII targets - trigger apoptosis in ERstressed macrophages. Moreover, we have made new discoveries related to the AngII receptor adaptor, beta-arrestin. Our work with PPARs provided new insight into how these drugs for obese diabetics affect advanced plaque progression. The mechanism of obesity-associated adipokines was advanced by showing that LPS, as a model of adiponectin-LPS complex, can suppress a pro-apoptotic branch of the UPR in vivo by the exact same mechanisms elucidated in vitro. Importantly, we have completed the first comprehensive study of adiponectin effects on atherosclerosis in mice and found that adiponectin by itself does not suppress atherogenesis. Moreover, we found that another obesity-associated adipokine - eNampt - may promote macrophage-associated disease processes in obese subjects. Finally, we have continued our studies on how a specific molecular event that could promote plaque necrosis and likely occurs in obesity - cleavage of the efferocytosis receptor Mertk - occurs in advanced human plaques. In summary, we have made substantial progress in understanding how obesity leads to accelerated heart disease at a molecular-cellular level. Future work spurred by these discoveries is likely to suggest novel therapeutic targets to prevent obesity-associated vascular disease in military personnel and in the general public.