Abstract P237: Mitochondrial GCN5L1 Promotes CypD Acetylation, Oxidative Stress, Endothelial Dysfunction And Hypertension

Abstract

Nearly half of adult population has hypertension which is a main risk factor for cardiovascular disease. Mitochondrial dysfunction contributes to hypertension and targeting mitochondria can potentially improve treatment of hypertension. We found hyperacetylation of mitochondrial Cyclophilin D (CypD) in essential hypertension and proposed that CypD acetylation can promote endothelial dysfunction and hypertension. CypD acetylation can be regulated by general control of amino acid synthesis 5 like 1 (GCN5L1) protein, therefore, we GCN5L1 can potentially promote endothelial dysfunction and hypertension. Western blot of aortic mitochondria showed an increased GCN5L1 level in hypertensive mice which was coupled with the reduction of Sirt3 deacetylase level resulting in 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. We reported pathogenic role of mitochondrial lipid oxidation products isolevuglandins (isoLGs) and scavenging of isoLGs with mitochondria-targeted mito2HOBA reduces mitochondrial acetylation. We tested if mitochondrial isoLGs contributes to acetylase/deacetylase imbalance driving CypD acetylation. It was found that mito2HOBA supplementation improves Sirt3 expression and reduces GCN5L1 level leading to normalization of GCN5L1/Sirt3 ratio and reduced CypD acetylation. To define the pathophysiological role of GCN5L1 in endothelial cells we tested if GCN5L1 depletion prevents cytokine-induced of mitochondrial oxidative stress. Indeed, treatment of human aortic endothelial cells with AngII+TNFα induces mitochondrial O 2 . -, however, GCN5L1 depletion using siRNA completely abrogated the cytokine-induced mitochondrial oxidative stress. To define the role GNC5L1 in pathogenesis of endothelial dysfunction we have developed new tamoxifen-inducible endothelial specific GNC5L1 knockout mice (Ec GNC5L1KO ). It was found that depletion of endothelial GCN5L1 reduces vascular production of mitochondrial O 2 . -, prevents inactivation of endothelial nitric oxide and preserves endothelial dependent relaxation in angiotensin II-infused Ec GNC5L1KO mice compared with wild-type littermates. These data support the pathogenic role of GNC5L1 in CypD acetylation and development of endothelial dysfunction.