Document Type

Article

Publication Date

12-7-2016

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This article has been peer reviewed. It is the author’s final published version in Scientific Reports

Volume 6, December 2016, Article number 37927.

The published version is available at DOI: 10.1038/srep37927. Copyright © Wang et al.

Abstract

Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which was completely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor. Mechanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apoptotic protein HAX-1, an effect attenuated by Ucf-101. Additionally, transfected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (H/R) induced apoptosis. Cyclosporine A (CsA), a mitochondrial permeability transition inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected transfected cells incompletely against H/R-induced caspase-3 activation. We report in vitro and in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction. Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria may protect against heart injury.

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This work is licensed under a Creative Commons Attribution 4.0 License.

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