title: Beta-adrenergic receptor mediated protection against doxorubicin-induced apoptosis in cardiomyocytes: the impact of high ambient glucose.
abstract: Recent studies have demonstrated that the beta2-adrenergic receptor (beta2AR)-Galphai signaling pathway exerts a cardiac antiapoptotic effect. The goals of this study were to determine the intracellular signaling factors involved in beta2AR-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), beta2AR 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 beta2AR-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 betaAR-induced PDGFR phosphorylation, Src kinase activity, and activation of PI3K signaling pathway; and 2) it partially attenuated beta2AR-induced antiapoptotic effect. These data provide in vitro evidence supporting a signaling cascade by which beta2AR exerts a protective effect against doxorubicin-induced apoptosis via sequential involvement of Galphai, Gbetagamma, Src, PDGFR, PI3K, and Akt. High ambient glucose significantly attenuates beta2AR-mediated cardioprotection by suppressing factors involved in this cascade including PDGFR, Src, and PI3K/Akt.
authors: Department of Pediatrics, Women and Infant's Hospital, 101 Dudley Street, Kilguss 122, Providence, Rhode Island 02905, USA.
authors: Naohiro
authors: N
authors: Yano
authors: Daisuke
authors: D
authors: Suzuki
authors: Masayuki
authors: M
authors: Endoh
authors: Andy
authors: A
authors: Tseng
authors: Joan P
authors: JP
authors: Stabila
authors: Bethany G
authors: BG
authors: McGonnigal
authors: Ting C
authors: TC
authors: Zhao
authors: James F
authors: JF
authors: Padbury
authors: Yi-Tang
authors: YT
authors: Tseng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000494:pharmacology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011943:Receptors, Adrenergic, beta; D004317:Doxorubicin; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D016392:Proto-Oncogene Proteins pp60(c-src); D005947:Glucose