Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway.
Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway.
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G 蛋白偶联受体激酶 2 (GRK2) 的心肌消融通过抗内在凋亡途径减少缺血/再灌注损伤。
DOI：
10.1371/journal.pone.0066234
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gao E
中科院分区：
文献类型：
--
作者：
Fan Q;Chen M;Zuo L;Shang X;Huang MZ;Ciccarelli M;Raake P;Brinks H;Chuprun KJ;Dorn GW 2nd;Koch WJ;Gao E
我们实验室的研究表明，降低心肌G蛋白偶联受体激酶2(GRK2)的活性和表达可以防止心肌梗死后心力衰竭的进展。由于GRK2在心肌细胞中似乎也是一种促死亡激酶，我们研究了心肌细胞特异性GRK2消融对心肌缺血/再灌注(I/R)损伤的急性反应的影响。为了做到这一点，我们利用了两个独立的GRK2基因敲除(KO)小鼠，其中GRK2基因在出生时结构性地或以成年小鼠在I/R之前发生的诱导方式仅在心肌细胞中缺失。这些GRK2基因敲除小鼠和相应的对照组小鼠接受假手术或冠状动脉结扎心肌缺血30分钟后再灌注24小时。超声心动图和血流动力学测量显示，两个GRK2KO系小鼠的I/R后心功能均有显著改善，与对照组相比，GRK2KO系小鼠的心肌梗死面积较小。GRK2KO组小鼠心肌I/R损伤后TUNEL阳性细胞数明显减少，caspase-3、caspase-9活性降低，但caspase-8活性下降。值得注意的是，我们发现，与相应的对照组相比，两个品系的GRK2 KO小鼠在I/R后心脏GRK2表达降低与胞浆细胞色素C水平显著降低相关。从机制上讲，降低GRK2表达的抗凋亡作用伴随着I/R损伤后Bcl2、Bclxl水平的升高和Akt的激活。这些发现在体外培养的心肌细胞和GRK2 mRNA沉默中重现。因此，降低心肌细胞GRK2的表达，至少部分通过Akt/Bcl2介导的线粒体保护来减少心肌细胞的凋亡，从而限制I/R诱导的损伤，促进缺血后的恢复，并涉及线粒体依赖的作用，巩固了GRK2作为促死亡激酶在心脏中的作用。
Studies from our lab have shown that decreasing myocardial G protein–coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R) injury. To do this we utilized two independent lines of GRK2 knockout (KO) mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post-I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post-ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl-2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart.
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影响因子：
20.1
作者：
Sohal, DS;Nghiem, M;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
20.1
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
通讯作者：
Koch WJ
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ
影响因子：
4.8
作者：
Gardai, SJ;Hildeman, DA;Henson, PM
通讯作者：
Henson, PM
影响因子：
64.5
作者：
Muzio, M;Chinnaiyan, AM;Dixit, VM
通讯作者：
Dixit, VM