title: Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction.
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.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zuo
authors.affiliation: Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Jiao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.|Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.|Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.|Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D000074923:High-Temperature Requirement A Serine Peptidase 2 / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D011506:Proteins / Q000378:metabolism*; D059748:Proteolysis; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D013871:Thiones / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: C491295:Hs1bp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011744:Pyrimidinones; D013871:Thiones; C501517:UCF 101; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse