Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension

• Published in: Journal of the American Heart Association Vol. 5; no. 6
• Main Authors: Eirin, Alfonso, Ebrahimi, Behzad, Kwon, Soon Hyo, Fiala, Justin A., Williams, Barbara J., Woollard, John R., He, Quan, Gupta, Ramech C., Sabbah, Hani N., Prakash, Y.S., Textor, Stephen C., Lerman, Amir, Lerman, Lilach O.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01-06-2016; Wiley
• Subjects: Animals; Antioxidants - pharmacology; Apoptosis - physiology; bendavia; Cardiolipins - metabolism; Cardiolipins - physiology; Cardiomyopathies - etiology; Cardiomyopathies - physiopathology; Cardiomyopathies - prevention & control; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Female; heart failure; hypertension; Hypertension, Renovascular - complications; Hypertension, Renovascular - physiopathology; Magnetic Resonance Angiography; Microvessels - physiology; mitochondria; Mitochondria, Heart - physiology; Mitochondrial Diseases - etiology; Mitochondrial Diseases - physiopathology; Mitochondrial Diseases - prevention & control; Multidetector Computed Tomography; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Original Research; Random Allocation; Renal Artery Obstruction - physiopathology; renal artery stenosis; renovascular hypertension; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Sus scrofa; Swine; tert-Butylhydroperoxide - pharmacology; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology; Ventricular Dysfunction, Left - prevention & control; Ventricular Remodeling - physiology; heart failure; bendavia; renal artery stenosis; hypertension; renovascular hypertension; mitochondria
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.115.003118

Background
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.
Methods and Results
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 Ca2+‐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.
Conclusions
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.