Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension

Abstract

BackgroundRenovascular 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 ResultsAfter 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.ConclusionsChronic 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.

Enhancing Mitochondrial Health to Treat Hypertension

“…In agreement, we have found that both cardiac and renal cardiolipin content is reduced in pigs with renovascular hypertension [11, 12]. Importantly, oxidation and consequent loss of cardiolipin destabilizes the ETC, triggering local generation of ROS and mitochondrial dysfunction [22].…”

“…Preservation of mitochondrial cardiolipin attenuated swine stenotic-kidney microvascular loss and injury, and improved renal oxygenation, hemodynamics, and function [12]. ELAM also blunted myocardial hypertrophy, improved left ventricular relaxation, and attenuated myocardial cellular and microvascular remodeling in these pigs [11]. Intravenous administration of ELAM in conjunction with renal revasculatization also improved cardiac and renal outcomes in pigs with renovascular hypertension [10, 13].…”

Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases

“…This protein is highly vulnerable to oxidative damage and subsequent loss, therefore leading to mitochondrial loss and contributing to development of cardiovascular disorders. The authors also demonstrate that restoration of cardiolipin improves cardiac function of pigs subjected to renovascular hypertension [43]. Therefore, all these observations indicate that the response of altering proton conductance depends on the etiology of hypertension.…”

The metabolic syndrome induces early changes in the swine renal medullary mitochondria

“…Renal expression of cardiolipin synthase (CRLS)-1 was measured by western blot (26), and mRNA expression of the cardiolipin remodeling enzyme taffazin (Taz)-1 (27) by real-time quantitative polymerase chain reaction (28). …”