Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension

Alfonso Eirin, Behzad Ebrahimi, Soon Hyo Kwon, Justin A. Fiala, Barbara J. Williams, John R. Woollard, Quan He, Ramech C. Gupta, Hani N. Sabbah, Y.s. Prakash, Stephen C Textor, Amir Lerman, Lilach O Lerman

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 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.

Original languageEnglish (US)
Article numbere003118
JournalJournal of the American Heart Association
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2016

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Renovascular Hypertension
Cardiolipins
Swine
tert-Butylhydroperoxide
Peptides
Wounds and Injuries
Sarcoplasmic Reticulum
Organelle Biogenesis
Cardiac Myocytes
Energy Metabolism
Thapsigargin
Multidetector Computed Tomography
Calcium-Transporting ATPases
Cardiomegaly
Mitochondrial Membranes
Left Ventricular Hypertrophy
Cardiomyopathies
Left Ventricular Function
Oxidative Stress
Magnetic Resonance Imaging

Keywords

  • Bendavia
  • Heart failure
  • Hypertension
  • Mitochondria
  • Renal artery stenosis
  • Renovascular hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension. / 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.

In: Journal of the American Heart Association, Vol. 5, No. 6, e003118, 01.06.2016.

Research output: Contribution to journalArticle

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. / Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension. In: Journal of the American Heart Association. 2016 ; Vol. 5, No. 6.
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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 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.",
keywords = "Bendavia, Heart failure, Hypertension, Mitochondria, Renal artery stenosis, Renovascular hypertension",
author = "Alfonso Eirin and Behzad Ebrahimi and Kwon, {Soon Hyo} and Fiala, {Justin A.} and Williams, {Barbara J.} and Woollard, {John R.} and Quan He and Gupta, {Ramech C.} and Sabbah, {Hani N.} and Y.s. Prakash and Textor, {Stephen C} and Amir Lerman and Lerman, {Lilach O}",
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AU - Eirin, Alfonso

AU - Ebrahimi, Behzad

AU - Kwon, Soon Hyo

AU - Fiala, Justin A.

AU - Williams, Barbara J.

AU - Woollard, John R.

AU - He, Quan

AU - Gupta, Ramech C.

AU - Sabbah, Hani N.

AU - Prakash, Y.s.

AU - Textor, Stephen C

AU - Lerman, Amir

AU - Lerman, Lilach O

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N2 - 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.

AB - 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.

KW - Bendavia

KW - Heart failure

KW - Hypertension

KW - Mitochondria

KW - Renal artery stenosis

KW - Renovascular hypertension

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