title: Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.
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.
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Zi-Lun
authors.initials: ZL
authors.lastname: Li
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: John A
authors.initials: JA
authors.lastname: Crane
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Kyra L
authors.initials: KL
authors.lastname: Jordan
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Aditya S
authors.initials: AS
authors.lastname: Pawar
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.).
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.affiliation: From the Division of Nephrology and Hypertension (X.Z., Z.-L.L., J.A.C., K.L.J., A.S.P., S.C.T., L.O.L.) and Division of Cardiovascular Diseases (A.L., L.O.L.), Mayo Clinic, Rochester, MN; and Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.-L.L.). lerman.lilach@mayo.edu.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D063269:Mitochondrial Turnover / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine
keywords: angiotensin receptor antagonists; autophagy; hypertension; hypertrophy, left ventricular; mitochondrial degradation; mitochondrial turnover
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