Penile endothelial dysfunction, impaired redox metabolism and blunted mitochondrial bioenergetics in diet-induced obesity: Compensatory role of H2O2

Abstract

Erectile dysfunction (ED) is considered an early manifestation of cardiovascular disease (CVD), endothelial dysfunction being the link between CVD and vasculogenic ED. Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. The aim of this study was to assess the impact of obesity on endothelial function, redox metabolism and mitochondrial bioenergetics of penile erectile tissue. Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. mtROS levels were measured by mitoSOX (O 2 .- ) and Amplex Red (H 2 O 2 ) fluorimetry, and the effect of the mitochondrial antioxidant mitoTempo on endothelium-dependent relaxations was tested. Mitochondrial respiration of intact microarteries was assessed with an Agilent Seahorse XF Pro analyzer, and the expression of mitochondria redox regulators was analysed by Western blot. Endothelium-dependent relaxations to acetylcholine (ACh) and to the mitoK ATP channel activator BMS191095 were reduced in penile arteries from HFD. mtROS levels were significantly increased and associated with upregulation of the endothelial NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in HFD erectile tissue. MitoTempo inhibited endothelial relaxations in control and HFD penile arteries. The bioenergetic profile was significantly reduced in HFD penile arteries compared to STD rats. Mitochondrial dysfunction with impaired bioenergetics and reduced mitoK ATP channel-mediated relaxation underlie endothelial and vascular dysfunction of erectile tissue in obesity, despite a compensatory mechanism that enhances Nox4-derived endothelial vasodilator mtROS. Therapeutic strategies aimed to stabilize mitochondria could restore redox balance and improve mitochondrial bioenergetics thus preventing oxidative stress and vascular dysfunction underlying metabolic disease associated ED. Obesity-induced penile endothelial dysfunction, impaired REDOX balance and mitochondrial dys function. See Discussion for details ACh, acetylcholine; EC, endothelial cell; ECT: electron chain transport; H2O2: hydrogen peroxyde; ERS, endoplasmic reticulum stress; NO, nitric oxide; eNOS: endothelial NO synthase; Nox4: NADPH oxidase 4; OCR: oxygen consume rate; PGC1ɑ: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; VSMC, vascular smooth muscle cell. ↑ increase; ↓ decrease;. • Obesity induces endothelial dysfunction, mitochondrial oxidative stress and blunted mitochondrial bioenergetics in penile arteries. • Vasodilator H₂O₂ released from endothelial mitochondrial Nox4 compensates for the impaired NO-mediated penile endothelial dysfunction induced by obesity. • Upregulation of endothelial Nox4 expression in penile arteries is associated to increased expression of PGC1α) in diet-induced obesity. • Penile endothelial dysfunction induced by obesity blunts arterial tone regulation mediated by mitoK ATP channels.