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Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension

Eirin, Alfonsoa; Williams, Barbara J.a; Ebrahimi, Behzada; Zhang, Xina; Crane, John A.a; Lerman, Amirb; Textor, Stephen C.a; Lerman, Lilach O.a,b

doi: 10.1097/HJH.0b013e3283658a53

Background: Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT.

Methods and results: After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05 mg/kg intravenously, 30 min before to 3.5 h after PTRS) or vehicle (n = 7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT + PTRS + Bendavia animals.

Conclusion: Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT.

aDivision of Nephrology and Hypertension, Department of Internal Medicine

bDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA

Correspondence to Lilach O. Lerman, MD, PhD, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: Lerman.Lilach@Mayo.Edu

Abbreviations: BOLD-MRI, blood oxygen level-dependent MRI; DHE, dihydroethidium; GABP, guanine adenine-binding protein; GFR, glomerular filtration rate; IVC, inferior vena cava; LV, left ventricle; LVMM, left ventricular muscle mass; MCP, monocyte chemoattractant protein; MDCT, multidetector computed tomography; mPTP, mitochondrial permeability transition pore; PGC, peroxisome proliferator-activated receptor gamma coactivator; PPAR, peroxisome proliferator-activated receptor; PRA, plasma renin activity; PTRS, percutaneous transluminal renal angioplasty and stenting; RVHT, renovascular hypertension; SMA, smooth muscle actin; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling

Received 29 March, 2013

Revised 30 May, 2013

Accepted 1 August, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins