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Hypertension. 2018 Jun;71(6):1143-1155. doi: 10.1161/HYPERTENSIONAHA.117.09405. Epub 2018 Apr 16.

Therapeutic Potential of a Novel Necrosis Inhibitor, 7-Amino-Indole, in Myocardial Ischemia-Reperfusion Injury.

Hwang IC1,2,3, Kim JY1,2,3, Kim JH2, Lee JE2,3, Seo JY2,3, Lee JW2, Park J1,2, Yang HM1,2,3, Kim SH4, Cho HJ1,2,3, Kim HS5,2,6,4.

Author information

1
From the Cardiovascular Center and Department of Internal Medicine, Seoul National University Hospital, Republic of Korea (I.-C.H., J.-H.K., J.P., H.-M.Y., H.-J.C., H.-S.K.).
2
National Leading Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Republic of Korea (I.-C.H., J.-Y.K., J.-H.K., J.-E.L., J.-Y.S., J.-W.L., J.P., H.-M.Y., H.-J.C., H.-S.K.).
3
Strategic Center of Cell and Bio Therapy for Heart, Diabetes, and Cancer, Seoul National University Hospital, Republic of Korea (I.-C.H., J.-Y.K., J.-E.L., J.-W.L., H.-M.Y., H.-J.C., H.-S.K.).
4
R&D Campus, LG Chem/Ltd., Daejeon, Republic of Korea (S.-H.K.).
5
From the Cardiovascular Center and Department of Internal Medicine, Seoul National University Hospital, Republic of Korea (I.-C.H., J.-H.K., J.P., H.-M.Y., H.-J.C., H.-S.K.) hyosoo@snu.ac.kr.
6
and Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Republic of Korea (H.-S.K.).

Abstract

Opening of mitochondrial permeability transition pore and Ca2+ overload are main contributors to myocardial ischemia-reperfusion injury, which paradoxically causes a wide variety of myocardial damage. We investigated the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial ischemia-reperfusion injury using in vitro and in vivo models. H9C2 rat cardiomyoblasts and neonatal cardiomyocytes were exposed to hypoxia-reoxygenation stress after pre-treatment with NecX, vitamin C, a combination of vitamin C and E, N-acetylcysteine, an apoptosis inhibitor (Z-VAD-fmk), or cyclosporine A. The main mechanism of cell death after hypoxia-reoxygenation stress was not apoptosis but necrosis, which was prevented by NecX. Protective effect of NecX was based on its potent reactive oxygen species scavenging activity, especially on mitochondrial reactive oxygen species. NecX preserved mitochondrial membrane potential through prevention of Ca2+ influx and inhibition of mitochondrial permeability transition pore opening, which was more potent than that by cyclosporine A. Using Sprague-Dawley rats exposed to myocardial ischemia for 45 minutes followed by reperfusion, we compared therapeutic efficacies of NecX with cyclosporine A, vitamin C, a combination of vitamin C and E, and 5% dextrose, each administered 5 minutes before reperfusion. NecX markedly inhibited myocardial necrosis and reduced fibrotic area to a greater extent than did cyclosporine A and other treated groups. In addition, NecX preserved systolic function and prevented pathological dilatory remodeling of left ventricle. The novel necrosis inhibitor has a significant protective effect against myocardial ischemia-reperfusion injury through inhibition of mitochondrial permeability transition pore opening, indicating that it is a promising candidate for cardioprotective adjunctive measure on top of reperfusion therapy.

KEYWORDS:

myocardial reperfusion injury; necrosis; reactive oxygen species; reperfusion injury

PMID:
29661840
PMCID:
PMC5959205
DOI:
10.1161/HYPERTENSIONAHA.117.09405
[Indexed for MEDLINE]
Free PMC Article

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