Abstract P343: Exercise-induces Mitochondrial Remodeling Prevents Angiotensin II-induced High Blood Pressure

Abstract

Objective: Regular practice of exercise is one of the most effective non-pharmacological interventions that improve vascular health, which is thought to be mediated by a repeated exposure of vessel walls to increased hemodynamic shear stress. The objective of this study was to investigate the effect of exercise preconditioning on endothelial mitochondria in an Ang II-induced hypertension model. Methods: In in vitro experiments, human aortic endothelial cells (HAECs) pre-exposed to laminar shear stress (LSS) (20 dyne/cm 2 , 48h) or situated under static flow were incubated with Ang II (100 nM, 2-6 h). In in vivo experiments, mice were singly housed with or without a voluntary running wheel for 7 weeks. Ang II (1 mg/kg per day) was infused using an osmotic pump for the last 2 weeks. Saline was used as a control. Results: Significant increase in the expression levels of key genes related to mitochondrial biogenesis and dynamics were observed under shear stress conditions. Mitochondrial content determined by mtDNA content and immunostaining were higher (2-fold, P < 0.01) in the shear-exposed cells. en face staining showed significantly higher mitochondrial content in the conduit and muscle feed arteries from exercise-trained mice compared with sedentary controls ( N = 10, P < 0.01) but not in the mesenteric arteries. Interestingly, LSS preconditioning attenuated Ang II-induced mitochondrial dysfunction in HAECs, which was evidenced by decreased mitoROS generation, increased ΔΨm, and reduced mtDNA damage. Likewise, in aortic tissues, Ang II-induced mitochondrial phenotypic changes (i.e. mitoROS production, mtDNA damage and ΔΨm reduction) were significantly reduced in exercise-preconditioned mice compared to sedentary controls. Moreover, exercise preconditioning completely blocked Ang II-induced blood pressure elevation assessed by telemetry (MAP mmHg: 160.5 ± 1.5 vs 115.0 ± 11.4). Conclusion: Taken together, high-magnitude LSS improves endothelial function by enhancing mtDNA integrity and mitochondrial function. These findings further support the idea that aerobic exercise is a prominent life-style modification strategy to prevent hypertension by targeting dysfunctional mitochondria in the vessel wall.