Increased Intracellular Lipid Accumulation in Cholesterol Loaded VSMCs upon MRTFA Overexpression

Abstract

Accumulation of lipids in in the arterial wall is a key feature of atherosclerosis. In atherosclerotic plaque from human and mouse origin it has recently become appreciated that more than 50% of total foam cells are derived from vascular smooth muscle cells (VSMCs) suggesting a much larger role for VSMCs in foam cell formation then previously assumed. The molecular mechanism behind this process and clinical significance remains yet to be elucidated. Myocardin Related Transcription Factor –A (MRTFA) is a transcriptional co‐activator that has been demonstrated to play a key role in pathological vascular remodelling including progression of atherosclerotic lesions. Here we aim to investigate the functional role of MRTFA on cholesterol loading of VSMCs.To address this, human coronary artery smooth muscle cells (HCASMCs) were loaded with cholesterol‐cyclodextrin complexes for 96 hours. Foam cell formation was evident by accumulation of intracellular Oil red O‐stained lipids. Notably, overexpression of MRTFA increased lipid accumulation with considerable build‐up of lipid droplets in the cytoplasm. Small molecule N‐cyclopropyl‐5‐(thiophen‐2‐yl)‐isoxazole‐3‐carboxamide (ISX), an activator of MRTFA‐driven transcription, further potentiated this effect. Although expression of macrophage markers by mouse SMCs following cholesterol loading has been demonstrated, we did not observe any consistent change in the expression of macrophage or SMCs markers in lipid loaded cells of human origin.These preliminary findings suggest that MRTFA in VSMCs plays a significant role in foam cell formation following cholesterol loading. A better understanding of the mechanisms for cholesterol handling may enable us to come up with better therapeutic strategies for prevention of cholesterol accumulation in the arterial walls and its clinical outcomes.Support or Funding InformationThis work was supported by the Swedish Research Council; the Swedish Heart and Lung Foundation, the Novo Nordisk Foundation, the Crafoord Foundation; the Royal Physiographic Society and the Magnus Bergvall Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.