Metoprolol increases the expression of beta(3)-adrenoceptors in the diabetic heart: effects on nitric oxide signaling and forkhead transcription factor-3.
We have previously shown that the beta-blocking drug metoprolol improves cardiac function in the streptozotocin-diabetic rat partly by inducing parallel improvements in cardiac metabolism and gene expression. beta-blockers have been previously reported to increase the expression of beta(1) and beta(2)-adrenoceptors, but their effects on the expression of beta(3)-adrenoceptors are unknown. The aim of the present study was to investigate whether metoprolol increases beta(3)-adrenoceptor expression and downstream Akt-mediated signaling. Left ventricular function was measured in paced isolated working hearts. beta(1), beta(2) and beta(3) adrenoceptor-expression levels were measured using Western blotting. Protein kinase A (PKA) and calcium/calmodulin dependent protein kinase II (CAMK-II) activities, as well as Akt phosphorylation, were measured as indices of downstream target activation. Chronic metoprolol treatment improved cardiac function and produced a marked increase in the expression of all three beta-adrenoceptor subtypes which was associated with a decrease in PKA activity and an increase in Akt phosphorylation. Akt-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) was not altered, but phosphorylation of the transcription factor FOXO-3 was increased. Metoprolol increased the expression of beta(1), beta(2) and beta(3) adrenoceptors, associated with repression of FOXO-3 expression. beta-adrenoceptor signaling shifted from PKA to Akt-mediated signaling, associated with phosphorylation of FOXO-3 but not eNOS.
Sharma
Vijay
V
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada V6T 1Z3.
Parsons
Hannah
H
Allard
Michael F
MF
McNeill
John H
JH
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D008790:Metoprolol