title: β-receptor antagonist treatment prevents activation of cell death signaling in the diabetic heart independent of its metabolic actions.
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.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Sharma
authors.forename: Arpeeta
authors.initials: A
authors.lastname: Sharma
authors.forename: Varun
authors.initials: V
authors.lastname: Saran
authors.forename: Pascal N
authors.initials: PN
authors.lastname: Bernatchez
authors.forename: Michael F
authors.initials: MF
authors.lastname: Allard
authors.forename: John H
authors.initials: JH
authors.lastname: McNeill
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D022461:Caveolins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D005227:Fatty Acids / Q000378:metabolism / Q000633:toxicity; D005355:Fibrosis / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D022461:Caveolins; D005227:Fatty Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D011943:Receptors, Adrenergic, beta; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D008790:Metoprolol