G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure

被引：194

作者：

Raake, Philip W. ^{[1
]}

Vinge, Leif E. ^{[1
]}

Gao, Erhe ^{[1
]}

Boucher, Matthieu ^{[1
]}

Rengo, Giuseppe ^{[1
]}

Chen, Xiongwen ^{[3
]}

DeGeorge, Brent R., Jr. ^{[1
]}

Matkovich, Scot ^{[4
]}

Houser, Steven R. ^{[3
]}

Most, Patrick ^{[1
]}

Eckhart, Andrea D. ^{[1
,2
]}

Dorn, Gerald W., II ^{[4
]}

Koch, Walter J. ^{[1
]}

机构：

[1] Thomas Jefferson Univ, Dept Med, Ctr Translat Med, George Zallie & Family Lab Cardiovasc Gene Therap, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Dept Med, Ctr Translat Med, Eugene Feiner Lab Vasc Biol & Thrombosis, Philadelphia, PA 19107 USA

[3] Temple Univ, Cardiovasc Res Ctr, Dept Physiol, Philadelphia, PA 19122 USA

[4] Washington Univ, Ctr Pharmacogenom, St Louis, MO USA

来源：

CIRCULATION RESEARCH | 2008年 / 103卷 / 04期

关键词：

heart failure; myocardial infarction; conditional gene targeting; GRK2;

D O I：

10.1161/CIRCRESAHA.107.168336

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

Myocardial G protein-coupled receptor kinase (GRK)2 is a critical regulator of cardiac beta-adrenergic receptor (beta AR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated beta AR with a GRK2-derived peptide that binds G(beta gamma) (beta ARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and beta ARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (alpha MHC-CreXGRK2 fl/fl) or only after administration of tamoxifen (alpha MHC-MerCreMerXGRK2 fl/fl) and examined the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 before coronary artery ligation prevented maladaptive postinfarction remodeling and preserved beta AR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in postinfarction cardiac remodeling and heart failure and support therapeutic approaches of targeting GRK2 or restoring beta AR signaling by other means to improve outcomes in heart failure.

引用

页码：413 / 422

页数：10

共 36 条

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