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J Am Heart Assoc. 2016 May 31;5(6). pii: e003118. doi: 10.1161/JAHA.115.003118.

Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension.

Author information

1
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
2
Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL.
3
Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, MI.
4
Department of Anesthesiology, Mayo Clinic, Rochester, MN.
5
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
6
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN lerman.lilach@mayo.edu.

Abstract

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 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.

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.

KEYWORDS:

bendavia; heart failure; hypertension; mitochondria; renal artery stenosis; renovascular hypertension

PMID:
27247333
PMCID:
PMC4937260
DOI:
10.1161/JAHA.115.003118
[Indexed for MEDLINE]
Free PMC Article

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