title: Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension.
abstract: Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH-induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury.
  
  
  
  After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert-butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin-sensitive sarcoplasmic reticulum Ca(2+)-ATPase activity that declined in HC-RVH normalized in MTP-treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP-treated pigs. In tBHP-treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics.
  
  
  
  Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC-RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Eirin
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Behzad
authors.initials: B
authors.lastname: Ebrahimi
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Soon Hyo
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Fiala
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Williams
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: John R
authors.initials: JR
authors.lastname: Woollard
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL.
authors.forename: Quan
authors.initials: Q
authors.lastname: He
authors.affiliation: Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI.
authors.forename: Ramech C
authors.initials: RC
authors.lastname: Gupta
authors.affiliation: Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN lerman.lilach@mayo.edu.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002308:Cardiolipins / Q000378:metabolism / Q000502:physiology*; D009202:Cardiomyopathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006978:Hypertension, Renovascular / Q000150:complications* / Q000503:physiopathology; D018810:Magnetic Resonance Angiography; D055806:Microvessels / Q000502:physiology; D008929:Mitochondria, Heart / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D061330:Multidetector Computed Tomography; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D012078:Renal Artery Obstruction / Q000503:physiopathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D034421:Sus scrofa; D013552:Swine; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000502:physiology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002308:Cardiolipins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D020122:tert-Butylhydroperoxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: bendavia; heart failure; hypertension; mitochondria; renal artery stenosis; renovascular hypertension