title: Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a.
abstract: Hyperglycemia-induced cardiomyocyte apoptosis contributes to diabetic cardiomyopathy. Glucagon-like peptide-1 (Glp1) receptor (Glp1r) agonists improve cardiac function and survival in response to ischemia-reperfusion and myocardial infarction. The present studies assessed whether Glp1r activation exerts direct cardioprotective effects in response to hyperglycemia. Treatment with the Glp1r agonist Exendin-4 attenuated apoptosis in neonatal rat ventricular cardiomyocytes cultured in high (33 mM) glucose. This protective effect was mimicked by the cAMP inducer forskolin. The Exendin-4 protective effect was blocked by the Glp1r antagonist Exendin(9-39) or the PKA antagonist H-89. Exendin-4 also protected cardiomyocytes from hydrogen peroxide (H2O2)-induced cell death. Cardiomyocyte protection by Exendin-4 was not due to reduced reactive oxygen species levels. Instead, Exendin-4 treatment reduced endoplasmic reticulum (ER) stress, demonstrated by decreased expression of glucose-regulated protein-78 (GRP78) and CCAT/enhancer-binding homologous protein (CHOP). Reduced ER stress was not due to activation of the unfolded protein response, indicating that Exendin-4 directly prevents ER stress. Exendin-4 treatment selectively protected cardiomyocytes from thapsigargin- but not tunicamycin-induced death. This suggests that Exendin-4 attenuates thapsigargin-mediated inhibition of the sarco/endoplasmic reticulum Ca(2+) ATPase-2a (SERCA2a). High glucose attenuates SERCA2a function by reducing SERCA2a mRNA and protein levels, but Exendin-4 treatment prevented this reduction. Exendin-4 treatment also enhanced phosphorylation of the SERCA2a regulator phospholamban (PLN), which would be expected to stimulate SERCA2a activity. In sum, Glp1r activation attenuates high glucose-induced cardiomyocyte apoptosis in association with decreased ER stress and markers of enhanced SERCA2a activity. These findings identify a novel mechanism whereby Glp1-based therapies could be used as treatments for diabetic cardiomyopathy.
authors.affiliation: Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute at Lake Nona, 6400 Sanger Rd., Orlando, FL 32837, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Younce
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008565:Membrane Proteins; D032383:Myocytes, Cardiac / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response; D014688:Venoms / Q000494:pharmacology*; D000099211:Phospholamban; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002135:Calcium-Binding Proteins; D005576:Colforsin; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D007004:Hypoglycemic Agents; D007546:Isoquinolines; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013449:Sulfonamides; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D014415:Tunicamycin; D014688:Venoms; D000099211:Phospholamban; C506948:Atp2a2 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000593835:Glp1r protein, rat; C018551:glucose-regulated proteins; C083773:exendin (9-39); C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide