Metaboloepigenetics and Atherosclerosis

PROJECT SUMMARY/ABSTRACT Atherosclerosis-related cardiovascular diseases (CVD) remain the leading cause of death worldwide. Current therapies mainly focus on managing the risk of atherosclerosis, rather than directly targeting the plaque- causing cells. However, these treatments still carry a significant residual risk for CVD, along with various side effects. Epigenetics and metabolism often occur early in various diseases and their close interaction has led to the emergence of the concept of “metaboloepigenetics”. Yet, the precise mechanisms by which they respond to environmental cues and contribute to chromatin modifications in atherosclerosis remains unaddressed. Global changes in the epigenome are driven in part by the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. This complex utilize the ATP energy to alter chromatin structure and modulate chromatin accessibility to various molecular players, such as transcriptional machinery, cofactors. The mutually exclusive BAF60 subunits serve as a link between the SWI/SNF complex and specific transcription factors. We have demonstrated that BAF60c is essential for preservation of vascular smooth muscle cells (VSMC) contractile phenotype by strengthening serum response factor (SRF) association with its coactivator P300 and the SWI/SNF complex. Our preliminary data further show that BAF60c is the most abundant BAF60 family member specifically expressed in VSMC in the normal arterial wall, and its expression decreases in human and mouse atherosclerotic lesions. Furthermore, BAF60c deficiency in VSMC aggravates atherosclerosis in mice. Knockdown of BAF60c leads to disturbed PPARγ activation and VSMC dysfunction, characteried by increased anaerobic glycolysis, oxidative stress, lipid accumulation, transition to macrophage-like cells and foam cells. Therefore, I hypothesized that BAF60c-PPARγ axis protects against atherogenesis through metaboloepigenetic modulation of VSMC homeostasis. Our long-term objectives are to elucidate how metabolo-epigenetic interplay modulates vascular cell behavior and fate in CVD and to uncover novel therapeutic avenues for CVD by targeting BAF60c-dependent metaboloepigenetic modifications. Specifically, Aim 1 will define the protective role of BAF60c-PPARγ axis in atherogenesis using both male and female VSMC-specific knockout and transgenic mice; Aim 2 will define the mechanisms underlying BAF60c-PPARγ axis in regulation of VSMC dysfunction in atherosclerosis in vitro. In summary, these studies will provide unique mechanistic insights into the role of Baf60c-dependent metaboloepigenetics in VSMC homeostasis during atherosclerosis. They will pave the way for further exploration of metaboloepigenetics in CVD. In addition, these findings will support future endeavors to target BAF60c-dependent metaboloepigenetics and to combine metabolism inhibitors and epigenetic modulators as potential therapeutic strategies for CVD.