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β-Adrenergic Receptor Mediated Protection against Doxorubicin-Induced Apoptosis in Cardiomyocytes: The Impact of High Ambient Glucose

Department of Pediatrics (N.Y., A.T., J.P.S., B.G.M., T.C.Z., J.F.P., Y.-T.T.), Women and Infant’s Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905; and Division of Nephrology and Metabolism (D.S., M.E.), Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan

Address all correspondence and requests for reprints to: Yi-Tang Tseng, Ph.D., Department of Pediatrics, Women and Infant’s Hospital, 101 Dudley Street, Kilguss 122, Providence, Rhode Island 02905. E-mail: ytseng{at}wihri.org.

Recent studies have demonstrated that the β₂-adrenergic receptor (β₂AR)-G_i signaling pathway exerts a cardiac antiapoptotic effect. The goals of this study were to determine the intracellular signaling factors involved in β₂AR-mediated protection against doxorubicin-induced apoptosis in H9c2 cardiomyocyte and explore the impact of high ambient glucose on the antiapoptotic effect. Under physiological glucose environment (100 mg/dl), β₂AR stimulation prevented doxorubicin-induced apoptosis, which was attenuated by cotreatment with wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, or transfection of a dominant-negative Akt. Inhibition of Src kinase with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine or cSrc small interfering RNA 32 also attenuated the antiapoptotic effect. Inhibition of platelet-derived growth factor receptor (PDGFR) with AG1296 reversed the β₂AR-induced antiapoptotic effect. Transfection of an active Src cDNA (Y529F) alone was sufficient to render the cells resistant to apoptosis, and the resistance was blocked by wortmannin. Transfection of an active PI3K minigene (iSH2-p110) alone also induced resistance to apoptosis, and the resistance was reversed by an Akt-inhibitor but not by AG1296. High ambient glucose (450 mg/dl) caused two major effects: 1) it significantly reduced βAR-induced PDGFR phosphorylation, Src kinase activity, and activation of PI3K signaling pathway; and 2) it partially attenuated β₂AR-induced antiapoptotic effect. These data provide in vitro evidence supporting a signaling cascade by which β₂AR exerts a protective effect against doxorubicin-induced apoptosis via sequential involvement of G_i, Gβ, Src, PDGFR, PI3K, and Akt. High ambient glucose significantly attenuates β₂AR-mediated cardioprotection by suppressing factors involved in this cascade including PDGFR, Src, and PI3K/Akt.