Selective β2-adrenoreceptor stimulation attenuates myocardial cell death and preserves cardiac function after ischemia-reperfusion injury.

Bhushan S, Kondo K, Predmore BL, Zlatopolsky M, King AL, Pearce C, Huang H, Tao YX, Condit ME, Lefer DJ
Arterioscler Thromb Vasc Biol. 2012 32 (8): 1865-74

PMID: 22652602 · PMCID: PMC3401356 · DOI:10.1161/ATVBAHA.112.251769

OBJECTIVE - β(2)-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β(2)-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability.

METHODS AND RESULTS - Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 µg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr(308) (P<0.001) and Ser(473) (P<0.01), and eNOS phosphorylation at Ser(1177) (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS(-/-) mice.

CONCLUSIONS - Our results indicate that β(2)-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.

MeSH Terms (14)

Adrenergic beta-2 Receptor Agonists Animals Cell Death Cyclic AMP-Dependent Protein Kinases Ethanolamines Formoterol Fumarate Ischemic Preconditioning, Myocardial Male Mice Mice, Inbred C57BL Myocardial Reperfusion Injury Myocytes, Cardiac Nitric Oxide Synthase Type III Proto-Oncogene Proteins c-akt

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