Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction.

Authors

Ke Wang, Capital Medical UniversityFollow
Yuexing Yuan, Thomas Jefferson UniversityFollow
Xin Liu, Capital Medical UniversityFollow
Wayne Bond Lau, Thomas Jefferson UniversityFollow
Lin Zuo, Shanxi Medical UniversityFollow
Xiaoliang Wang, Shanxi Medical University
Lu Ma, Capital Medical UniversityFollow
Kun Jiao, Capital Medical University
Jianyu Shang, Capital Medical UniversityFollow
Wen Wang, Capital Medical UniversityFollow
Xinliang Ma, Capital Medical University; Shanxi Medical UniversityFollow
Huirong Liu, Capital Medical UniversityFollow

Document Type

Article

Publication Date

12-7-2016

Comments

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.

Recommended Citation

Wang, Ke; Yuan, Yuexing; Liu, Xin; Lau, Wayne Bond; Zuo, Lin; Wang, Xiaoliang; Ma, Lu; Jiao, Kun; Shang, Jianyu; Wang, Wen; Ma, Xinliang; and Liu, Huirong, "Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction." (2016). Department of Emergency Medicine Faculty Papers. Paper 51.
https://jdc.jefferson.edu/emfp/51

Creative Commons License

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

PubMed ID

27924873