Pim-1 Kinase Protects Mitochondrial Integrity in Cardiomyocytes

被引：90

作者：

Borillo, Gwynngelle A. ^{[1
]}

Mason, Matt ^{[1
]}

Quijada, Pearl ^{[1
]}

Voelkers, Mirko ^{[1
]}

Cottage, Christopher ^{[1
]}

McGregor, Michael ^{[1
]}

Din, Shabana ^{[1
]}

Fischer, Kimberlee ^{[1
]}

Gude, Natalie ^{[1
]}

Avitabile, Daniele ^{[1
]}

Barlow, Steven ^{[1
]}

Alvarez, Roberto ^{[1
]}

Truffa, Silvia ^{[1
]}

Whittaker, Ross ^{[1
]}

Glassy, Matthew S. ^{[1
]}

Gustafsson, Asa B. ^{[1
]}

Miyamoto, Shigeki ^{[2
]}

Glembotski, Christopher C. ^{[1
]}

Gottlieb, Roberta A. ^{[1
]}

Brown, Joan Heller ^{[2
]}

Sussman, Mark A. ^{[1
]}

机构：

[1] San Diego State Univ, San Diego State Heart Inst, San Diego, CA 92182 USA

[2] Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA

来源：

CIRCULATION RESEARCH | 2010年 / 106卷 / 07期

关键词：

Pim-1; mitochondria; cardiomyocyte; apoptosis; BCL-X-L; REPERFUSION INJURY; PERMEABILITY TRANSITION; CYTOCHROME-C; CELL-DEATH; APOPTOSIS; BAX; SURVIVAL; HEART; NUCLEAR;

D O I：

10.1161/CIRCRESAHA.109.212035

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: Cardioprotective signaling mediates antiapoptotic actions through multiple mechanisms including maintenance of mitochondrial integrity. Pim-1 kinase is an essential downstream effector of AKT-mediated cardioprotection but the mechanistic basis for maintenance of mitochondrial integrity by Pim-1 remains unexplored. This study details antiapoptotic actions responsible for enhanced cell survival in cardiomyocytes with elevated Pim-1 activity. Objective: The purpose of this study is to demonstrate that the cardioprotective kinase Pim-1 acts to inhibit cell death by preserving mitochondrial integrity in cardiomyocytes. Methods and Results: A combination of biochemical, molecular, and microscopic analyses demonstrate beneficial effects of Pim-1 on mitochondrial integrity. Pim-1 protein level increases in the mitochondrial fraction with a corresponding decrease in the cytosolic fraction of myocardial lysates from hearts subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Cardiac-specific overexpression of Pim-1 results in higher levels of antiapoptotic Bcl-XL and Bcl-2 compared to samples from normal hearts. In response to oxidative stress challenge, Pim-1 preserves the inner mitochondrial membrane potential. Ultrastructure of the mitochondria is maintained by Pim-1 activity, which prevents swelling induced by calcium overload. Finally, mitochondria isolated from hearts created with cardiac-specific overexpression of Pim-1 show inhibition of cytochrome c release triggered by a truncated form of proapoptotic Bid. Conclusion: Cardioprotective action of Pim-1 kinase includes preservation of mitochondrial integrity during cardiomyopathic challenge conditions, thereby raising the potential for Pim-1 kinase activation as a therapeutic interventional approach to inhibit cell death by antagonizing proapoptotic Bcl-2 family members that regulate the intrinsic apoptotic pathway. (Circ Res. 2010;106:1265-1274.)

引用

页码：1265 / U201

页数：17

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