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Myocardial ₁-adrenergic receptor polymorphisms affect functional recovery after ischemic injury

¹Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ²Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland

Submitted 23 August 2005 ; accepted in final form 3 November 2005

Association studies suggest ₁-adrenergic receptor (₁-AR) polymorphisms are disease modifiers in heart failure. The Arg389 variant has increased coupling to G_s in transfected cells and evokes enhanced ventricular function in transgenic mice. Here, we assessed the differential effects of the human Gly389 and Arg389 ₁-AR polymorphisms on myocardial recovery after ischemic injury. Function was studied in transgenic mice with cardiac-specific expression of either human Gly389 or Arg389 ₁-AR at baseline and after 20 min of ex vivo ischemia and reperfusion (I/R). In 3-mo-old mice of either genotype, there was poor recovery after I/R (38% vs. 68% for nontransgenic). Paradoxically, at 6 mo of age, functional recovery remained severely depressed in Gly389 hearts (32%) but was similar to nontransgenic for Arg389 hearts (60%). In Arg389 hearts, agonist-promoted adenylyl cyclase activities were depressed by 35% at 6 mo of age, and G protein-coupled receptor kinase (GRK) activity was increased by approximately twofold compared with Gly389. Furthermore, I/R evoked an approximately threefold increase in ERK2 phosphorylation in Arg389 but an approximately twofold decrease in Gly389 hearts. Individually, these changes have been shown to mitigate I/R injury; thus the Arg389-₁-AR uniquely evokes specialized pathways that act to protect against I/R injury. The improved recovery of function after I/R in Arg389 hearts relative to Gly389 appears to be due to an adaptive multimechanism program with allele-specific alterations in receptor signaling, GRK activity, and ERK2. Thus genetic variation of the human ₁-AR may play a role in cardiac functional recovery after ischemic injury.

genetics; adenylyl cyclase; mitogen-activated protein kinase; G protein-coupled receptor kinase

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