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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

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Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.

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Patient iPSCs identify vascular smooth muscle AADAC as protective against atherosclerosis

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