Toyohara T, Roudnicky F, Florido MHC, Nakano T, Yu H, Katsuki S, Lee M, Meissner T, Friesen M, Davidow LS, Ptaszek L, Abe T, Rubin LL, Pereira AC, Aikawa M, Cowan CA. Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis. Cell Stem Cell. 2020 May 14.

Citation

Toyohara T, Roudnicky F, Florido MHC, Nakano T, Yu H, Katsuki S, Lee M, Meissner T, Friesen M, Davidow LS, Ptaszek L, Abe T, Rubin LL, Pereira AC, Aikawa M, Cowan CA. 2020. Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis. Cell stem cell. 27(1):147-157.e7. Pubmed: 32413331 DOI:S1934-5909(20)30157-0

Abstract

Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), 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). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.

Related Faculty

Lee Rubin, Ph.D.

Rubin Lab

Lee Rubin investigates the key molecular mediators of a variety of neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.