EFFECTS OF VOLUNTARY EXERCISE PRECONDITIONING ON LEFT VENTRICULAR SYSTOLIC FUNCTION AND CARDIAC AUTOPHAGY IN ANGIOTENSIN II-INDUCED HYPERTENSIVE MICE

Abstract

Purpose/Hypothesis: Hypertension is a clinical condition with persistent elevation or raised blood pressure and accounts for approximately 9.4 million deaths every year. Exercise is one of the most effective non-pharmacological interventions and is emphasized in the current treatment guidelines for Hypertension from the World Health Organization. Currently, there is no consensus on whether autophagy is compensatory or causative in the transition from adaptive left ventricular hypertrophy to maladaptive left ventricular remodeling. It also remains unclear whether exercise preconditioning is sufficient to target autophagy for therapeutic benefits in Angiotensin II-induced hypertensive mice. The purpose of this study was to examine the effect of voluntary running exercise preconditioning on systolic function and autophagy in the heart in angiotensin II-induced hypertensive mice. Methods: Forty C57BL6/J mice were divided into 4 groups; Sedentary Sham (Sed), Sedentary Angiotensin II (SAII), Exercise Sham (Ex), Exercise Angiotensin II (ExAII). Animals in the exercise group were singly-housed and familiarized with a running wheel for 3 days prior to the study commencing. Exercise mice had access to a voluntary running wheel for 7 weeks. Ang II was infused at a constant rate using an implantable osmotic pump for the last two weeks of the experimental period. Results: Heart weight was greater in SAII, Ex and ExAII groups compared to Sed mice. Mice in Ex and ExAII groups had no significant differences in running distance or running speed. Ang II infusion caused a significantly higher thickness in the left ventricular posterior wall in diastole (LVPWd) in SAII mice which was further exacerbated in ExAII mice, creating a greater hypertrophy effect. Exercise training significantly raised systolic function as measured by ejection fraction (EF%) and fractional shortening (FS%), and exercise training prevented a significant percent reduction of EF% that was observed in SAII mice. SAII mice had significant elevations in fibrosis when compared to Sed and Ex mice, while ExAII mice had significant elevation in fibrosis when compared to Ex mice. In response to exercise training, DRP1 mRNA expression was significantly reduced, and in SAII mice protein expression of LC3II/I ratio was significantly higher which was attenuated in ExAII mice. Conclusion: Ang II resulted in a greater cardiac hypertrophy, and exercise training prevented the significant reduction in pre-post AII infusion in ejection fraction, preserving LV systolic function in ExAII mice. Ang II significantly raised the formation of autophagic machinery in SAII mice, which was attenuated in ExAII mice. This was not accompanied by a reduction in p62, indicating a possible impairment in autophagic flux in the left ventricle. Voluntary running did not alter basal autophagy, but did reduce LC3 autophagosome formation in ExAII mice and was able to attenuate the reduction in systolic function seen in SAII mice.