Abstract 619: Beta-Blockers Switch Catecholamine Activation of MAPKs from Maladaptive Beta-Adrenergic-p38 to Adaptive Alpha-1-Adrenergic-ERK
Beta-adrenergic receptor (AR) antagonists (beta-blockers) increase survival in heart failure, but the signaling mechanisms are uncertain. The extracellular signal-regulated kinase (ERK) mitogen activated protein kinase (MAPK) is anti-apoptotic in myocytes, whereas the MAPK p38 can be pro-apoptotic. Here we tested the hypothesis that beta-blockers switch catecholamine signaling from maladaptive p38 to adaptive ERK.
Methods. Cultured myocytes from adult male C57BL/6J mice were stimulated acutely with the natural catecholamines norepinephrine (NE) or epinephrine (EPI) (2 uM). Adult mice had LAD ligation to cause myocardial infarction (MI), and osmotic pump infusion of the beta-blocker propranolol (16 mg/kg/day) or vehicle from weeks 2 to 4 after MI. MAPK phosphorylation (activation) was measured by immunoblot, and cardiac function by conscious echo.
Results. In myocytes, NE or EPI without beta-blocker decreased ERK phosphorylation (vehicle 100%, NE 13%, EPI 4%; n=3; p<0.05) and the beta-AR agonist isoproterenol (1 uM) had a similar effect (15%). The beta-AR mediated decrease of ERK was prevented by okadaic acid (100 nM; n=4; p<0.05), suggesting that a beta-AR decreased ERK by activating protein phosphatase type-2A. In direct contrast, NE or EPI in the presence of propranolol (2 uM) caused ERK activation (NE 389%, EPI 448%; n=4; p<0.05). ERK activation by NE or EPI with propranolol was abolished by the alpha-AR blocker prazosin (200 nM; n=3; p<0.05), and in alpha-1 knockout myocytes (n=2), indicating an alpha-1 response. NE or EPI without beta-blocker also increased p38 phosphorylation (5-fold; n=3; p<0.05), and p38 activation was eliminated by propranolol. In the MI model of heart failure with elevated catecholamines, the non-infarcted remote myocardium had increased p38 activity and decreased ERK. Propranolol infusion for 2 weeks caused 4-fold ERK activation in remote myocardium (n=4; p<0.05), and reduced p38 activation (3% of vehicle; n=2). Propranolol improved function (ejection fraction increased 16%; p<0.05).
Conclusion. Catecholamines in vitro and in vivo inhibit myocyte anti-apoptotic ERK and activate pro-apoptotic p38 via beta-ARs. Beta-blockers switch catecholamine signaling to ERK activation via an alpha-1-AR and inhibit p38.