β-receptor antagonist treatment prevents activation of cell death signaling in the diabetic heart independent of its metabolic actions.

Titleβ-receptor antagonist treatment prevents activation of cell death signaling in the diabetic heart independent of its metabolic actions.
Publication TypeJournal Article
Year of Publication2011
AuthorsSharma, V, Sharma, A, Saran, V, Bernatchez, PN, Allard, MF, McNeill, JH
JournalEur J Pharmacol
Volume657
Issue1-3
Pagination117-25
Date Published2011 Apr 25
ISSN1879-0712
KeywordsAdrenergic beta-Antagonists, Animals, bcl-Associated Death Protein, Caspase 3, Caveolins, Cell Death, Cyclic AMP-Dependent Protein Kinases, Diabetes Mellitus, Experimental, Fatty Acids, Fibrosis, Heart, Male, Metoprolol, Myocardium, Oxidation-Reduction, Oxidative Stress, Phosphorylation, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Rats, Rats, Wistar, Receptors, Adrenergic, beta, Signal Transduction
Abstract

We have previously shown that metoprolol improves function in the diabetic heart, associated with inhibition of fatty acid oxidation and a shift towards protein kinase B signaling. The aim of this study was to determine the relative importance of these metabolic and signaling effects to the prevention of cellular damage. Diabetes was induced in male Wistar rats by a single IV injection of 60mg/kg streptozotocin, and treated groups received 15mg/kg/day metoprolol delivered subcutaneously by osmotic pumps. Echocardiography was performed 6weeks after streptozotocin injection, and the hearts immediately excised for histological and biochemical measurements of lipotoxicity, apoptosis, signaling and caveolin/caspase interactions. Metoprolol improved stroke volume and cardiac output, associated with attenuation of TUNEL staining and a more modest attenuation of caspase-3; however, the positive TUNEL staining was not associated with an increase in apoptosis or cell regeneration markers. Metoprolol inhibited CPT-1 without affecting CD36 translocation, associated with increased accumulation of triglycerides and long chain acyl CoA in the cytoplasm, and no effect on oxidative stress. Metoprolol induced a shift from protein kinase A to protein kinase B-mediated signaling, associated with a shift in the phosphorylation patterns of BCl-2 and Bad which favored BCl-2 action. Metoprolol also increased the interaction of activated caspase-3 with caveolins 1 and 3 outside caveolae. The actions of metoprolol on fatty acid oxidation do not prevent lipotoxicity; its beneficial effect is more likely to be due to pro-survival signaling and sequestration of activated caspase-3 by caveolins.

DOI10.1016/j.ejphar.2011.01.044
Alternate JournalEur. J. Pharmacol.
PubMed ID21296063
Grant List / / Canadian Institutes of Health Research / Canada