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

Akhter, Shahab A., Karen M. D’Souza, Natalia N. Petrashevskaya, Jeanne Mialet-Perez, and Stephen B. Liggett. Myocardial 1-adrenergic receptor polymorphisms affect functional recovery after ischemic injury. Am J Physiol Heart Circ Physiol 290: H1427–H1432, 2006; doi:10.1152/ajpheart.00908.2005.—Association studies suggest 1-adrenergic receptor ( 1-AR) polymorphisms are disease modifiers in heart failure. The Arg389 variant has increased coupling to Gs 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 Arg3891-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.