Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a

• Published in: American Journal of Physiology: Cell Physiology 2013-03, Vol.304 (6), p.C508-C518
• Main Authors: Younce, Craig W, Burmeister, Melissa A, Ayala, Julio E
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Calcium-Binding Proteins - metabolism; Cells, Cultured; Colforsin - pharmacology; Diabetic Cardiomyopathies - metabolism; Endoplasmic Reticulum Stress - drug effects; Enzyme Activation; Enzyme kinetics; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose - metabolism; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins; Hydrogen Peroxide - pharmacology; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacology; Isoquinolines - pharmacology; Membrane Proteins; Molecules; Myocytes, Cardiac - physiology; Oxidative Stress - drug effects; Peptide Fragments - pharmacology; Peptides - pharmacology; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Rats; Receptors, Glucagon - agonists; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - metabolism; RNA, Messenger - biosynthesis; Rodents; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Sulfonamides - pharmacology; Thapsigargin - pharmacology; Transcription Factor CHOP - biosynthesis; Transcription Factor CHOP - metabolism; Tunicamycin - pharmacology; Unfolded Protein Response; Venoms - pharmacology
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00248.2012

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.