Alpha 1A‐Adrenergic Receptor Signaling Protects the Heart From Ischemic Injury Through an ERK‐Dependent Mechanism

Abstract

Brief periods of ischemia stimulate an endogenous mechanism in the heart that protects the myocardium from subsequent episodes of prolonged ischemia. This process, called “ischemic preconditioning”, is mimicked by signaling through α1A‐adrenergic receptors (ARs). Extracellular regulated kinases (ERK‐1 and ERK‐2) have been implicated in ischemic preconditioning. Therefore, we used mice expressing constitutively active mutant α1A‐adrenergic receptors (CAM α1A‐ARs) to determine whether α1A‐ARs protect the heart from ischemic injury through an ERK‐dependent mechanism. Western blots demonstrated that phosphorylation of ERK‐1 and ERK‐2 is significantly increased in CAM α1A‐AR hearts relative to nontransgenic hearts. Isolated hearts were perfused using the Langendorf method, and contractile function was monitored by an intraventricular balloon. Hearts isolated from CAM α1A‐AR or nontransgenic mice were subjected to 30 min ischemia and 1 hour reperfusion. Contractile function of CAM α1A‐AR hearts, but not nontransgenic hearts, completely recovered from 30 min ischemia. Perfusion with U0126 (MEK inhibitor) prior to the onset of ischemia blocked ERK phosphorylation and abolished the ability of CAM α1A‐AR hearts to recover from ischemia. These data support the conclusion that α1A‐ARs protect the heart from ischemic injury through an ERK‐dependent signaling pathway.(This study was supported by a Bower, Bennet, & Bennet Endowed Research Chair Award from Ohio Northern University).