Depletion of Mitochondrial Cyclophilin D in Endothelial and Smooth Muscle Cells Attenuates Vascular Dysfunction and Hypertension.

Abstract

Hypertension is a major risk factor of cardiovascular disease affecting nearly half of adult population. It is associated with mitochondrial dysfunction and understanding these mechanisms is important to develop new therapies. Cyclophilin D (CypD) promotes mitochondrial swelling and dysfunction. The objective of this study is to test if CypD depletion attenuates vascular dysfunction and hypertension using endothelial and smooth muscle-specific CypD knockout mice in angiotensin II model of vascular dysfunction and hypertension. Our results show that depletion of endothelial CypD prevents angiotensin II-induced impairment of endothelial-dependent vasorelaxation, preserves endothelial nitric oxide and mitochondrial respiration, attenuates hypertension, vascular oxidative stress and vascular metabolic glycolytic-switch. Depletion of smooth muscle CypD slightly reduces angiotensin II-induced hypertension, protects vascular nitric oxide and vasorelaxation, decreases vascular superoxide, diminishes angiotensin II-induced vascular glycolysis, hypertrophy and fibrosis. These data suggest "metabolic" and "redox" crosstalk between endothelial and smooth muscle cells. Endothelial CypD depletion reduces not only endothelial glycolysis but also attenuates smooth muscle cell glycolytic switch. Smooth muscle CypD depletion reduced not only smooth muscle glycolysis, but it also attenuated endothelial glycolysis. Vascular oxidative stress was inhibited both in EcCypDKO and SmcCypDKO mice, therefore, cell-specific CypD depletion had "global" antioxidant effect in vasculature. Our results support a novel function of mitochondrial CypD in regulation of superoxide and metabolism in vascular smooth muscle and endothelial cells which affect endothelial barrier and smooth muscle vascular functions. We suggest that blocking vascular CypD reduces vascular oxidative stress, improves vascular metabolism and vascular function which may be beneficial in cardiovascular disease.