Endothelial derived extracellular vesicles from obese/hypertensive adults increase factors associated with hypertrophy and fibrosis in cardiomyocytes.

Obesity and hypertension, independently and combined, are associated with increased risk of heart failure and heart failure-related morbidity and mortality. Interest in circulating endothelial cell-derived microvesicles (EMVs) has intensified due to their involvement in the development and progression of endothelial dysfunction, atherosclerosis, and cardiomyopathy. The experimental aim of this study was to determine, in vitro, the effects of EMVs isolated from obese/hypertensive adults on key proteins regulating cardiomyocyte hypertrophy (cardiac troponin T [cTnT], a-actinin, nuclear factor-kB [NF-kB]) and fibrosis (transforming growth factor [TGF]-b, collagen1-a1) as well as endothelial nitric oxide synthase (eNOS) expression and NO production. EMVs (CD144+ microvesicles) were isolated from plasma by flow cytometry in: 12 normal weight/normotensive (8M/4F; age: 56±5 yr; BMI: 23.3±2.0 kg/m2 ; BP: 117/74±4/5 mmHg) and 12 obese/hypertensive (8M/4F; 57±5 yr; 31.7±1.8 kg/m2 ; 138/83±8/7 mmHg). Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were cultured and treated with EMVs from either normal weight/normotensive or obese/hypertensive adults for 24 hr. Expression of cTnT (64.1+13.9 vs 29.5+7.8 AU), a-actinin (66.0+14.7 vs. 36.2+10.3 AU), NF-kB (166.3+13.3 vs 149.5+8.8 AU), phosphorylated-NF-kB (226.1+25.2 vs 179.1+25.5 AU) and TGF-ß (62.1+13.3 vs. 23.5+8.8 AU) were significantly higher and eNOS activation (16.4+4.3 vs. 24.8+3.7 AU) and nitric oxide production (6.8+1.2 vs. 9.6+1.3 µmol/L) were significantly lower in iPSC-CMs treated with EMVs from obese/hypertensive compared with normal weight/normotensive adults. These data indicate that EMVs from obese/hypertensive adults induce a cardiomyocyte phenotype prone to hypertrophy, fibrosis and reduced nitric oxide production, central factors associated with heart failure risk and development.