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.
Am J Physiol Cell Physiol. 2013 Mar;304(6):C508-18. doi: 10.1152/ajpcell.00248.2012. Epub 2013 Jan 9.
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.
高血糖诱导的心肌细胞凋亡导致糖尿病心肌病。胰高血糖素样肽-1（GLP-1）受体（GLP1R）激动剂改善了缺血再灌注和心肌梗死后的心脏功能和存活率。本研究评估了 GLP1R 激活是否对高血糖产生直接的心脏保护作用。用 GLP1R 激动剂 Exendin-4 处理，可减轻高糖（33mM）培养的新生大鼠心室心肌细胞的凋亡。这种保护作用可被 cAMP 诱导剂 forskolin 模拟。GLP1R 拮抗剂 Exendin(9-39)或蛋白激酶 A 拮抗剂 H-89 阻断 Exendin-4 的保护作用。Exendin-4 还可防止心肌细胞因过氧化氢（H2O2）诱导的细胞死亡。Exendin-4 对心肌细胞的保护作用并非由于活性氧水平降低所致。相反，Exendin-4 处理降低了葡萄糖调节蛋白-78（GRP78）和 CCAT/增强子结合同源蛋白（CHOP）的表达，从而减轻内质网（ER）应激。内质网应激的减少不是由于未折叠蛋白反应的激活，这表明 Exendin-4 直接阻止内质网应激。Exendin-4 处理选择性地保护心肌细胞免受 thapsigargin 而不是衣霉素诱导的死亡。这表明 Exendin-4 可减轻 thapsigargin 对肌浆/内质网 Ca2+-ATPase-2a（SERCA2a）的抑制作用。高葡萄糖通过降低 SERCA2a mRNA 和蛋白水平来减弱 SERCA2a 的功能，但 Exendin-4 处理可防止这种降低。Exendin-4 处理还增强了 SERCA2a 调节剂肌浆球蛋白轻链磷酸酶（PLN）的磷酸化，这将刺激 SERCA2a 的活性。总之，GLP1R 激活可减轻高血糖诱导的心肌细胞凋亡，同时减少内质网应激和增强 SERCA2a 活性的标志物。这些发现确定了一种新的机制，即基于 GLP1 的治疗方法可用于治疗糖尿病心肌病。
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