Abstract 15288: Mitochondrial Injury in Cardiomyopathy of Neurogenic Hypertension: Role of MiR-18a-5p/HIF-1a Axis

Abstract

Hypertension increases the risk of heart disease, and key hallmark features of hypertensive heart disease is sympatho-excitation and mitochondrial injury. However, the molecular intermediary link between enhanced sympatho-excitation and cardiac mitochondrial injury remains unclear. Sprague-Dawley rats (250-300g) were subjected to a central infusion of Ang II (20ng/min for 14days, 0.5μl/h, i.c.v.; neurogenic hypertension (NG-HTN)) or isotonic saline (0.9% saline, i.c.v; Control (Con)) through osmotic mini-pumps. Mitochondrial injury and cardiac remodeling were assessed using Western blot, histology, immunocytochemistry and electron microscopy. Sympatho-excitatory effect on mitochondrial injury was examined in in vitro by administration of norepinephrine (NE) on H9c2 rat cardiomyocytes. Our NG-HTN rat model exhibited increased sympatho-excitaton and hypertension. Concomitantly, there was reduced miRNA-18a-5p (NG-HTN: 0.65±0.05 vs. Con: 1.06±0.04 vs.), but increased HIF-1α levels in the heart (NG-HTN: 1.82±0.4 vs. Con: 0.88±0.13). Increased mitochondrial untranslated protein response (UPR mt ) marker HSP60 (NG-HTN: 1.22±0.08 vs. Con: 0.81±0.07) indicated mitochondrial proteinopathy and proteotoxic stress associated with increased mito-ROS and altered mitochondrial oxidative phosphorylation. Further, there was reduced mitochondrial biogenesis and fusion, but increased mitochondrial fission, coupled with impaired mitochondrial TIM-TOM translocase performance in NG-HTN hearts. Electron microscopy revealed mitochondrial injury in NG-HTN hearts, linked with hypertrophic cardiomyopathy and fibrosis remodeling. Our In-silico data showed increased NE decreased miR-18a-5p to target HIF-1α, and corroborated mitochondrial injury and cardiomyocyte hypertrophy in, in vitro studies. In conclusion, these results demonstrate that enhanced sympatho-excitation contributes to reduced miR-18a-5p causing increased HIF-1α in the heart leading to mitochondrial proteotoxic stress and metabolic shift, which underlies mitochondrial injury. This study identifies the key molecular intermediary links that can potentially be manipulated for therapeutic benefits for pathological cardiac remodeling in clinical HTN.