Double- Stranded RNA- Dependent Protein Kinase Deficiency Protects the Heart From Systolic Overload- Induced Congestive Heart Failure

被引：44

作者：

Wang, Huan ^{[1
,2
]}

Xu, Xin ^{[1
,2
]}

Fassett, John ^{[1
,2
]}

Kwak, Dongmin ^{[1
,2
]}

Liu, Xiaoyu ^{[1
,2
,4
]}

Hu, Xinli ^{[1
,2
,5
]}

Falls, Therasa J. ^{[6
]}

Bell, John C. ^{[6
]}

Li, Hongliang ^{[7
]}

Bitterman, Peter ^{[3
]}

Bache, Robert J. ^{[1
,2
]}

Chen, Yingjie ^{[1
,2
]}

机构：

[1] Univ Minnesota, Sch Med, Cardiovasc Div, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Sch Med, Lillehei Heart Inst, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Sch Med, Div Pulm, Minneapolis, MN 55455 USA

[4] Tongji Univ, Shanghai Peoples Hosp 10, Shanghai 200092, Peoples R China

[5] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China

[6] Ottawa Hosp, Res Inst, Ottawa, ON, Canada

[7] Wuhan Univ, Dept Cardiol, Renmin Hosp, Wuhan 430072, Peoples R China

来源：

CIRCULATION | 2014年 / 129卷 / 13期

基金：

美国国家卫生研究院;

关键词：

apoptosis; heart failure; inflammation; innate immunity; protein kinases R; translation initiation; translation regulation; CARDIOMYOCYTE APOPTOSIS; PRESSURE-OVERLOAD; OXIDATIVE STRESS; SENTINEL KINASE; TNF-ALPHA; PKR; ACTIVATION; PHOSPHORYLATION; DYSFUNCTION; EXPRESSION;

D O I：

10.1161/CIRCULATIONAHA.113.002209

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Double-stranded RNA-dependent protein kinase (PKR) is a eukaryotic initiation factor 2 kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independently of translational regulation. Congestive heart failure is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular hypertrophy and the development of congestive heart failure has not been examined. Methods and Results We observed increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with congestive heart failure. To determine the impact of PKR on the development of congestive heart failure, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction. Although heart size increased similarly in wild-type and PKR knockout mice after transverse aortic constriction, PKR knockout mice exhibited very little pulmonary congestion, well-preserved left ventricular ejection fraction and contractility, and significantly less myocardial fibrosis compared with wild-type mice. Bone marrow-derived cells from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, whereas bone marrow-derived cells from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated transverse aortic constriction-induced tumor necrosis factor- expression and leukocyte infiltration and lowered cardiac expression of proapoptotic factors (Bax and caspase-3), so that PKR knockout hearts were more resistant to transverse aortic constriction-induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against tumor necrosis factor-- or lipopolysaccharide-induced apoptosis. Conclusion PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.

引用

页码：1397 / 1406

页数：10

共 37 条

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