Metabolically stressed adipocytes: mediators of cardioprotection via extracellular vesicle-mediated transport of oxidatively damaged mitochondria.

Abstract

Obesity is a known risk factor for cardiovascular disease (CVD), including heart failure and ischemia. However, although the incidence of CVD is higher in obese humans, numerous studies have found that obese individuals with CVD have a better prognosis than lean individuals, a phenomenon known as the “obesity paradox” (1). Adipose tissue has a well-defined role as an endocrine organ that differs by anatomical location [e.g., inguinal white adipose tissue (WAT), perigonadal WAT, interscapular brown adipose tissue (BAT), etc.] as well as adipocyte cell content (white vs. brown vs. beige), and recent work has focused on the adipose-cardiac signaling axis to decipher the endocrine mechanisms of adipocytes. We and others have recently reviewed adipose tissue-derived signals that are known to directly impact the myocardium (2–4). Some of these adipose-derived endocrine signals are mediated by small extracellular vesicles (sEVs) that can deliver diverse cargo, including RNA, protein, and lipids (4). However, the cardiac effect of adipose-derived sEVs is not always consistent. Multiple recent studies describe EV-mediated delivery of specific microRNA (miRNA) from adipose-derived stem cells that impact mouse models of cardiac ischemic injury (5–9). BAT-derived EVs blunt obesity-induced declines in cardiac function, but their delivered EVs were shown to accumulate mainly in the liver, spleen, and lungs, and the direct effects on the myocardium were not investigated (10). Conversely, EVs secreted from WAT in response to PPARγ activation induce hypertrophic signaling in neonatal cardiac myocytes via transport of miRNA (11). sEVs isolated from epicardial adipose tissue were associated with atrial fibrillation in humans, were sufficient to induce cardiac fibrosis when injected into rats, and implicated sEV-mediated delivery of pro-fibrotic miRNAs as a potential mechanism (12).