Double-stranded RNA-dependent protein kinase deficiency protects the heart from systolic overload-induced congestive heart failure.
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 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.


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-α 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-α- or lipopolysaccharide-induced apoptosis.


CONCLUSIONS
PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.
Cardiovascular Division and Lillehei Heart Institute (H.W., X.X., J.F., D.K., X.L., X.H., R.J.B., Y.C.) and Pulmonary Division (P.B.), University of Minnesota Medical School, Minneapolis; Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L.); Institute of Molecular Medicine, Peking University, Beijing, China (X.H.); Ottawa Hospital Research Institute, Ottawa, ON, Canada (T.J.F., J.C.B.); and Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (H.L.).
Huan
H
Wang
Xin
X
Xu
John
J
Fassett
Dongmin
D
Kwak
Xiaoyu
X
Liu
Xinli
X
Hu
Therasa J
TJ
Falls
John C
JC
Bell
Hongliang
H
Li
Peter
P
Bitterman
Robert J
RJ
Bache
Yingjie
Y
Chen
D000328:Adult; D000368:Aged; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D006984:Hypertrophy / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D019892:eIF-2 Kinase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D019892:eIF-2 Kinase
apoptosis; heart failure; inflammation; innate immunity; protein kinases R; translation initiation; translation regulation