Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN.
Hypertension. 2014 Jan;63(1):128-35. doi: 10.1161/HYPERTENSIONAHA.113.02313. Epub 2013 Oct 28.
In response to several stresses, including nutrient deprivation, general control nonderepressible 2 kinase (GCN2) attenuates mRNA translation by phosphorylating eukaryotic initiation factor 2α(Ser51). Energy starvation is known to exacerbate congestive heart failure, and eukaryotic initiation factor 2α(Ser51) phosphorylation is increased in the failing heart. However, the effect of GCN2 during the evolution of congestive heart failure has not been tested. In this study, we examined the influence of GCN2 expression in response to a cardiac stress by inducing chronic pressure overload with transverse aortic constriction in wild-type and GCN2 knockout mice. Under basal conditions, GCN2 knockout mice had normal left ventricular structure and function, but after transverse aortic constriction, they demonstrated less contractile dysfunction, less increase in lung weight, less increase in lung inflammation and vascular remodeling, and less myocardial apoptosis and fibrosis compared with wild-type mice, despite an equivalent degree of left ventricular hypertrophy. As expected, GCN2 knockout attenuated transverse aortic constriction-induced cardiac eukaryotic initiation factor 2α(Ser51) phosphorylation and preserved sarcoplasmic reticulum Ca(2+) ATPase expression compared with wild-type mice. Interestingly, the expression of the antiapoptotic protein Bcl-2 was significantly elevated in GCN2 knockout hearts, whereas in isolated neonatal cardiomyocytes, selective knockdown of GCN2 increased Bcl-2 protein expression and enhanced myocyte resistance to an apoptotic stress. Collectively, our data support the notion that GCN2 impairs the ventricular adaptation to chronic pressure overload by reducing Bcl-2 expression and increasing cardiomyocyte susceptibility to apoptotic stimuli. Our findings suggest that strategies to reduce GCN2 activity in cardiac tissue may be a novel approach to attenuate congestive heart failure development.
在应对包括营养缺乏在内的多种应激时，一般调控非阻遏蛋白 2 激酶（GCN2）通过磷酸化真核起始因子 2α（Ser51）来抑制 mRNA 翻译。众所周知，能量饥饿会加重充血性心力衰竭，衰竭心脏中真核起始因子 2α（Ser51）的磷酸化增加。然而，GCN2 在充血性心力衰竭进展过程中的作用尚未得到检验。在这项研究中，我们通过横主动脉缩窄诱导慢性压力超负荷，在野生型和 GCN2 敲除小鼠中检测了 GCN2 表达对心脏应激的影响。在基础条件下，GCN2 敲除小鼠具有正常的左心室结构和功能，但在横主动脉缩窄后，与野生型小鼠相比，它们表现出较少的收缩功能障碍、肺重量增加减少、肺炎症和血管重塑增加、心肌细胞凋亡和纤维化减少，尽管左心室肥厚程度相当。正如预期的那样，与野生型小鼠相比，GCN2 敲除小鼠减弱了横主动脉缩窄诱导的心脏真核起始因子 2α（Ser51）磷酸化，并保留了肌浆网 Ca2+ATP 酶的表达。有趣的是，GCN2 敲除小鼠心脏中抗凋亡蛋白 Bcl-2 的表达显著升高，而在分离的新生心肌细胞中，GCN2 的选择性敲低增加了 Bcl-2 蛋白的表达，并增强了心肌细胞对凋亡应激的抵抗力。总之，我们的数据支持这样的观点，即 GCN2 通过降低 Bcl-2 的表达和增加心肌细胞对凋亡刺激的敏感性，损害心室对慢性压力超负荷的适应。我们的发现表明，降低心脏组织中 GCN2 活性的策略可能是减轻充血性心力衰竭发展的一种新方法。
