Abstract
Metabolic syndrome (MetS) leads to cardiac vascular injury, which may reflect in increased retention of endothelial progenitor cells (EPCs). Coronary endothelial cell (EC) mitochondria partly regulate vascular function and structure. We hypothesized that chronic mitoprotection would preserve EC mitochondria and attenuate coronary vascular injury and dysfunction in swine MetS. Pigs were studied after 16 wk of diet-induced MetS, MetS treated for the last 4 wk with the mitochondria-targeted peptide elamipretide (ELAM; 0.1 mg/kg sc once daily), and lean controls ( n = 6 each). Cardiac remodeling and function were assessed in vivo by multidetector-computed tomography (CT), and coronary artery and sinus blood samples were collected. EC mitochondrial density, apoptosis, oxidative stress, endothelial nitric oxide synthase immunoreactivity, myocardial microvascular density (three-dimensional microcomputed tomography), and coronary endothelial function (organ bath) were assessed ex vivo. The number and arteriovenous gradient of CD34+/KDR+ EPCs were calculated by FACS (a negative net gradient indicating EPC retention). MetS and MetS + ELAM pigs developed similar MetS (obesity, hyperlipidemia, insulin resistance, and hypertension). EC mitochondrial density decreased in MetS animals compared with lean animals but normalized in MetS + ELAM animals. ELAM also attenuated EC oxidative stress and apoptosis and improved subendocardial microvascular density. ELAM-induced vasculoprotection was reflected by decreased coronary retention of EPCs. ELAM also partly improved endothelial nitric oxide synthase immunoreactivity, coronary endothelial function, and vessel maturity, whereas myocardial perfusion was unaffected. Chronic mitoprotection improved coronary EC mitochondrial density and decreased vascular remodeling and dysfunction. However, additional mitochondria-independent mechanisms likely contribute to MetS-induced cardiac vascular injury. NEW & NOTEWORTHY The present study shows that chronic mitoprotection preserved coronary endothelial cell mitochondria and decreased vascular injury, subendocardial microvascular loss, coronary retention of endothelial progenitor cells, and release of markers of vascular injury. However, myocardial perfusion remained blunted, suggesting that additional mitochondria-independent mechanisms likely contribute to metabolic syndrome-induced cardiac vascular injury.