title: Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death : Omi/HtrA2 and aged heart injury.
abstract: Survival after acute myocardial infarction is decreased in elderly patients. The enhanced rates of apoptosis in the aging heart exacerbate myocardial ischemia/reperfusion (MI/R) injury. We have recently demonstrated that the X-linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats' hearts. XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO. However, the implicative role of XIAP, Omi/HtrA2, and Smac/DIABLO to aging-related MI/R injury has not been previously investigated. In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion. MI/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size, and increased myocardial apoptosis (TUNEL and caspase-3 activity). Then, the XIAP, Omi/HtrA2, and Smac/DIABLO protein and mRNA expression was detected. XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R. Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R. However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts. Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R. Treatment with ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects. Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis.
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An Men, P.O. Box 907, Beijing, 100069, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Liu
authors.forename: Jue
authors.initials: J
authors.lastname: Tian
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Quan
authors.forename: Haibo
authors.initials: H
authors.lastname: Xu
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020287:In Situ Nick-End Labeling; D008297:Male; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C490770:Tra2b protein, rat; D051636:X-Linked Inhibitor of Apoptosis Protein; D000068103:Serine-Arginine Splicing Factors; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2