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Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.

Hypertension (Dallas, Tex. : 1979) (2014-04-23)
Xin Zhang, Zi-Lun Li, John A Crane, Kyra L Jordan, Aditya S Pawar, Stephen C Textor, Amir Lerman, Lilach O Lerman
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

SAFC
L-Valine
Sigma-Aldrich
L-Valine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
L-Valine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%
Sigma-Aldrich
L-Valine, reagent grade, ≥98% (HPLC)
Supelco
L-Valine, certified reference material, TraceCERT®
Valsartan, European Pharmacopoeia (EP) Reference Standard
USP
Valsartan, United States Pharmacopeia (USP) Reference Standard
Supelco
L-Valine, Pharmaceutical Secondary Standard; Certified Reference Material
Valsartan for peak identification, European Pharmacopoeia (EP) Reference Standard
Supelco
Valsartan, Pharmaceutical Secondary Standard; Certified Reference Material
Valine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Valsartan, ≥98% (HPLC)
Valsartan for system suitability, European Pharmacopoeia (EP) Reference Standard