Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms.
Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms.
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DOI：
10.1161/circresaha.110.221010
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发表时间：
2010-10-29
影响因子：
20.1
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Brinks H;Boucher M;Gao E;Chuprun JK;Pesant S;Raake PW;Huang ZM;Wang X;Qiu G;Gumpert A;Harris DM;Eckhart AD;Most P;Koch WJ
某些G蛋白偶联受体（GPCRs）激活促存活激酶并随后产生一氧化氮（NO）可保护缺血再灌注损伤（I/R）模型中的心肌。GPCR信号通路由GPCR激酶（GRKs）调节，并且GRK 2已被证明是正常和病理性心脏功能中的关键分子。已知心脏GRK 2活性的丧失至少部分通过心脏β-肾上腺素能受体（βAR）信号传导的正常化来阻止心力衰竭（HF）的进展。已经用GRK 2敲除小鼠以及GRK 2活性的肽抑制剂βARKct的表达进行了慢性HF研究。本研究采用大鼠急性心肌缺血再灌注模型，探讨GRK 2及其活性在急性心肌缺血损伤中的作用。我们使用心脏特异性GRK 2和βARKct表达转基因小鼠证明，GRK 2对体内心肌I/R损伤的有害作用，βARKct赋予心脏保护作用。GRK 2过表达小鼠的I/R后梗死面积较大（45.0±2.8%对对照组的31.3±2.3%），而βARKct小鼠的梗死面积显著较小（16.8± 1.3%，p<0.05）。重要的是，在体内细胞凋亡被发现是一致的这些相互影响后I/R心肌损伤时，GRK 2活性水平的改变。此外，这些结果通过较高的Akt活化和通过βARKct诱导NO产生来反映，并且这些抗凋亡/存活作用可以在体外重现。有趣的是，β 2AR的选择性拮抗作用消除了β ARKct介导的心脏保护作用，表明该GPCR上增强的GRK 2活性对心肌细胞存活有害。通过增加Akt活性减少急性缺血性心肌损伤的新效应显著增加了βARKct抑制GRK 2对慢性HF以及急性缺血性损伤病症的治疗潜力。
Activation of pro-survival kinases and subsequent nitric oxide (NO) production by certain G protein-coupled receptors (GPCRs) protects myocardium in ischemia-reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases (GRKs) and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function. A loss of cardiac GRK2 activity is known to arrest progression of heart failure (HF), at least in part by normalization of cardiac β-adrenergic receptor (βAR) signaling. Chronic HF studies have been done with GRK2 knockout mice as well as expression of the βARKct, a peptide inhibitor of GRK2 activity. This study was conducted to examine the role of GRK2 and its activity during acute myocardial ischemic injury using an I/R model. We demonstrate, using cardiac-specific GRK2 and βARKct expressing transgenic mice, a deleterious effect of GRK2 on in vivo myocardial I/R injury with βARKct imparting cardioprotection. Post-I/R infarct size was greater in GRK2 overexpressing mice (45.0±2.8% vs. 31.3±2.3% in controls) and significantly smaller in βARKct mice (16.8±1.3%, p<0.05). Importantly, in vivo apoptosis was found to be consistent with these reciprocal effects on post-I/R myocardial injury when levels of GRK2 activity were altered. Moreover, these results were reflected by higher Akt activation and induction of NO production via βARKct and these anti-apoptotic/survival effects could be recapitulated in vitro. Interestingly, selective antagonism of β2ARs abolished βARKct-mediated cardioprotection suggesting that enhanced GRK2 activity on this GPCR is deleterious to cardiac myocyte survival. The novel effect of reducing acute ischemic myocardial injury via increased Akt activity adds significantly to the therapeutic potential of GRK2 inhibition with the βARKct to not only chronic HF but also potentially in acute ischemic injury conditions.