title: α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake.
abstract: While α(1)-adrenergic receptors (ARs) have been previously shown to limit ischemic cardiac damage, the mechanisms remain unclear. Most previous studies utilized low oxygen conditions in addition to ischemic buffers with glucose deficiencies, but we discovered profound differences if the two conditions are separated. We assessed both mouse neonatal and adult myocytes and HL-1 cells in a series of assays assessing ischemic damage under hypoxic or low glucose conditions. We found that α(1)-AR stimulation protected against increased lactate dehydrogenase release or Annexin V(+) apoptosis under conditions that were due to low glucose concentration not to hypoxia. The α(1)-AR antagonist prazosin or nonselective protein kinase C (PKC) inhibitors blocked the protective effect. α(1)-AR stimulation increased (3)H-deoxyglucose uptake that was blocked with either an inhibitor to glucose transporter 1 or 4 (GLUT1 or GLUT4) or small interfering RNA (siRNA) against PKCδ. GLUT1/4 inhibition also blocked α(1)-AR-mediated protection from apoptosis. The PKC inhibitor rottlerin or siRNA against PKCδ blocked α(1)-AR stimulated GLUT1 or GLUT4 plasma membrane translocation. α(1)-AR stimulation increased plasma membrane concentration of either GLUT1 or GLUT4 in a time-dependent fashion. Transgenic mice overexpressing the α(1A)-AR but not α(1B)-AR mice displayed increased glucose uptake and increased GLUT1 and GLUT4 plasma membrane translocation in the adult heart while α(1A)-AR but not α(1B)-AR knockout mice displayed lowered glucose uptake and GLUT translocation. Our results suggest that α(1)-AR activation is anti-apoptotic and protective during cardiac ischemia due to glucose deprivation and not hypoxia by enhancing glucose uptake into the heart via PKCδ-mediated GLUT translocation that may be specific to the α(1A)-AR subtype.
authors.affiliation: a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Shi
authors.affiliation: a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Papay
authors.affiliation: a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA.
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Perez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D050505:Mutant Proteins; D018340:Receptors, Adrenergic, alpha-1; D003847:Deoxyglucose; D051745:Protein Kinase C-delta; D005947:Glucose
keywords: Adrenergic receptor; cardiac; glucose transporter
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