Valsartan Regulates Myocardial Autophagy and Mitochondrial Turnover in Experimental Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 64; no. 1; pp. 87 - 93
• Main Authors: Zhang, Xin, Li, Zi-Lun, Crane, John A, Jordan, Kyra L, Pawar, Aditya S, Textor, Stephen C, Lerman, Amir, Lerman, Lilach O
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-07-2014; Lippincott Williams & Wilkins
• Subjects: Animals; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Arterial hypertension. Arterial hypotension; Autophagy - drug effects; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Blood Pressure - physiology; Cardiology. Vascular system; Heart - drug effects; Heart - physiopathology; Hypertension, Renovascular - drug therapy; Hypertension, Renovascular - metabolism; Hypertension, Renovascular - physiopathology; Medical sciences; Mitochondria - drug effects; Mitochondria - physiology; Mitochondrial Turnover - drug effects; Myocardium - metabolism; Swine; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Valine - analogs & derivatives; Valine - pharmacology; Valine - therapeutic use; Valsartan; Ventricular Remodeling - drug effects; Imidazole derivatives; Tetrazole derivatives; Valsartan; Peptide hormone; Cardiovascular disease; mitochondrial degradation; Degradation; Octapeptide; Mitochondria; Regulation(control); Turnover; angiotensin receptor antagonists; left ventricular; Angiotensin II; Valine derivatives; Cardiology; Biological receptor; Hypertension; autophagy; mitochondrial turnover; Experimental study; Left ventricle; Renin angiotensin system; Biphenyl derivatives; Aminoacid; Myocardium; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Circulatory system; Hypertrophy; hypertrophy, left ventricular; hypertension
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.02151

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The angiotensin II receptor blocker, valsartan, lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with valsartan (320 mg/d) or conventional triple therapy (reserpine+hydralazine+hydrochlorothiazide) for 4 weeks after 6 weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function, and myocardial oxygenation and microcirculation were assessed by multidetector computer tomography, blood oxygen level–dependent MRI, and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension–induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure–independent manner.