EPAC1 Boosts Macrophage Appetite: Implication of EPAC1 in Foam Cell Formation during Atherosclerosis

With the increasing age of the global population, cardiovascular diseases (CVD) is the leading contributor of morbidity and mortality in growing patient populations. Thus, further elucidating the pathophysiology and developing novel treatments for CVD are critical to combat this urgent unmet medical need. The cAMP second messenger, is a major stress‐response signal found to play an important role in cardiovascular functions. Moreover, the downstream contribution of the exchange protein directly activated by cAMP 1 (EPAC1) in the development of atherosclerosis has yet to be explored. Genetic ablation of EPAC1 in atherosclerosis prone LDb (Ldlr −/− /Apobec1 −/− ) mice were developed as a model to investigate the functional consequences attributable to loss of EPAC1 in the pathogenesis of atherosclerosis. Remarkably, absence of EPAC1 protected against atherosclerotic lesion development compared to mice expressing EPAC1. One prevalent source attributing to atherosclerotic pathologies is chronic arterial inflammation, implicating innate immunological responders, such as macrophages. Within the lesion, macrophages are subject to a multitude of inflammatory cytokines and initiate engulfment of oxidized lipids that trigger lipid‐laden foam cell formation. Although the presence of foam cells is observed to further perpetuate macrophage aggregation and subsequent lesion advancement, the precise molecular mechanisms governing formation of foam cells and initial progression of atherosclerosis are still not fully understood. Recent evidence demonstrates EPAC1 participating in functions downstream of cAMP during phagocytosis, and thus may be involved in macrophage accumulation of oxidized‐LDL. Therefore, we hypothesize that loss of EPAC1 could attenuate atherosclerotic lesion development, in part by disrupting physiological endocytosis of oxidized‐LDL in macrophages. Indeed, further investigation demonstrates reduced phagocytosis and lipid‐burden in bone‐marrow derived macrophages not expressing EPAC1 when exposed to oxidized‐LDL. These results depict an unidentified functional role for EPAC1 in endocytosis of oxidized lipids, and suggest targeting EPAC1 may be beneficial in attenuating atherosclerotic lesion development in patients. Support or Funding Information This work was supported by the U.S. National Institutes of Health (NIH) Grants R01‐GM066170 and R35‐GM122536. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .