Patient iPSCs identify vascular smooth muscle AADAC as protective against atherosclerosis

ABSTRACT: Cardiovascular disease (CVD) is the most common cause of death in patients with type II diabetes mellitus (T2DM). Although susceptibility to CVD is different for every patient, why some patients with T2DM develop CVD while others are protected has not yet been clarified. Patient-derived induced pluripotent stem cells (iPSCs) have been utilized to reveal the influence of genotype on phenotype and have the potential to connect a clinical phenotype to a causal gene. Using T2DM patient-derived iPSCs, we found that in patients protected from CVD there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC) in vascular smooth muscle cells (VSMCs). To investigate the function of AADAC in CVD, we overexpressed this esterase in human primary coronary artery VSMCs and VSMCs differentiated from iPSCs and observed that the number of lipid droplets per cell was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids such as triacylglycerol and diacylglycerol and an increase in membrane phospholipids suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration, proliferation, and apoptosis were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein (Apo) E knockout mice overexpressing VSMC-specific Aadac showed significant amelioration of atherosclerotic lesions. Isolated VSMCs from these mice also displayed decreased lipid droplets, storage lipids, cell migration, proliferation, and apoptosis, all of which were consistent with human data. Our findings suggest that elevated AADAC expression in VSMCs protects T2DM patients from CVD. This study also highlights the potential of patient-derived iPSCs to investigate disease associated phenotypes as a means of elaborating the molecular mechanisms underlying disease pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113969 | GEO | 2020/05/18

REPOSITORIES: GEO