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

Abstract
Background—Double stranded RNA-dependent protein kinase (PKR) is a eukaryotic initiation factor 2α kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independent of translational regulation. Congestive heart failure (CHF) is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular (LV) hypertrophy and development of CHF has not been examined.
Methods and Results—We observed an increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with CHF. To determine the impact of PKR in the development of CHF, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction (TAC). Though heart size increased similarly in wild-type and PKR knockout mice after TAC, PKR knockout mice exhibited very little pulmonary congestion, well preserved LV ejection fraction and contractility, and significantly less myocardial fibrosis as compared to wild-type mice. Bone marrow-derived cells (BMDCs) from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, while BMDCs from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated TAC-induced TNF-α expression and leukocyte infiltration, and lowered cardiac expression of pro-apoptotic factors (Bax and Caspase-3) so that PKR knockout hearts were more resistant to TAC-induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against TNF-α or LPS-induced apoptosis.
Conclusions—PKR is a maladaptive factor up-regulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis and development of CHF.
- Received February 25, 2013.
- Revision received January 2, 2014.
- Accepted January 13, 2014.
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- Double Stranded RNA-Dependent Protein Kinase Deficiency Protects the Heart from Systolic Overload-Induced Congestive Heart FailureHuan Wang, Xin Xu, John Fassett, Dongmin Kwak, Xiaoyu Liu, Xinli Hu, Theresa J. Falls, John C. Bell, Hongliang Li, Peter Bitterman, Robert J. Bache and Yingjie ChenCirculation. 2014;CIRCULATIONAHA.113.002209, originally published January 24, 2014https://doi.org/10.1161/CIRCULATIONAHA.113.002209
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- Double Stranded RNA-Dependent Protein Kinase Deficiency Protects the Heart from Systolic Overload-Induced Congestive Heart FailureHuan Wang, Xin Xu, John Fassett, Dongmin Kwak, Xiaoyu Liu, Xinli Hu, Theresa J. Falls, John C. Bell, Hongliang Li, Peter Bitterman, Robert J. Bache and Yingjie ChenCirculation. 2014;CIRCULATIONAHA.113.002209, originally published January 24, 2014https://doi.org/10.1161/CIRCULATIONAHA.113.002209