双链RNA依赖性蛋白激酶缺乏可保护心脏免受收缩期负荷过重诱导的充血性心力衰竭。

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

作者信息

Wang Huan, Xu Xin, Fassett John, Kwak Dongmin, Liu Xiaoyu, Hu Xinli, Falls Therasa J, Bell John C, Li Hongliang, Bitterman Peter, Bache Robert J, Chen Yingjie

机构信息

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.).

出版信息

Circulation. 2014 Apr 1;129(13):1397-406. doi: 10.1161/CIRCULATIONAHA.113.002209. Epub 2014 Jan 24.

DOI:10.1161/CIRCULATIONAHA.113.002209

PMID:24463368

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3972332/

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 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-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.

CONCLUSION

PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.

摘要

背景

双链RNA依赖性蛋白激酶（PKR）是一种真核起始因子2α激酶，在应激条件下抑制mRNA翻译。PKR还独立于翻译调控介导炎症和凋亡信号传导。充血性心力衰竭与心肌细胞肥大、炎症和凋亡相关，但PKR在左心室肥大和充血性心力衰竭发展中的作用尚未得到研究。

方法与结果

我们观察到充血性心力衰竭患者和小鼠的心肌PKR表达增加以及PKR易位至细胞核。为了确定PKR对充血性心力衰竭发展的影响，将PKR基因敲除小鼠和野生型小鼠暴露于横断主动脉缩窄所产生的压力超负荷环境中。尽管横断主动脉缩窄后野生型和PKR基因敲除小鼠的心脏大小增加相似，但与野生型小鼠相比，PKR基因敲除小鼠的肺淤血很少，左心室射血分数和收缩性保存良好，心肌纤维化明显较少。野生型小鼠的骨髓来源细胞并未消除PKR基因敲除小鼠中观察到的心脏保护作用，而PKR基因敲除小鼠的骨髓来源细胞对野生型小鼠没有心脏保护作用。机制上，PKR基因敲除减弱了横断主动脉缩窄诱导的肿瘤坏死因子-α表达和白细胞浸润，并降低了促凋亡因子（Bax和半胱天冬酶-3）的心脏表达，因此PKR基因敲除的心脏对横断主动脉缩窄诱导的心肌细胞凋亡更具抵抗力。分离的心肌细胞中PKR缺失也赋予了对肿瘤坏死因子-α或脂多糖诱导的凋亡的保护作用。