Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
PLoS One. 2013 May 22;8(5):e65147. doi: 10.1371/journal.pone.0065147. Print 2013.
Cardiac injury is a common pathological change frequently accompanied by diabetes mellitus. Recently, some evidence indicated that calcium-sensing receptor (CaSR) expressed in the cardiac tissue. However, the functional role of CaSR in diabetic cardiac injury remains unclear. The present study was designed to investigate the relationship between CaSR activation and diabetes-induced cardiac injury. Diabetic model was successfully established by administration of streptozotocin (STZ) in vivo, and cardiomyocyte injury was simulated by 25.5 mM glucose in vitro. Apoptotic rate, intracellular calcium concentration (Ca²⁺) and the expression of Bcl-2, Bax, extracellular signal-regulated protein kinase (ERK), c-Jun NH₂-terminal protein kinase (JNK), and p38 were examined. We demonstrated a significant increase in left ventricular end-diastolic pressure (LVEDP) as well as decrease in maximum rate of left ventricular pressure rise and fall (±dp/dtmax), and left ventricular systolic pressure (LVSP), apoptosis of cardiomyocytes was also observed by TUNEL staining. In vitro, 25.5 mM glucose-induced apoptosis was detected by flow cytometry in neonatal rat cardiomyocytes. Further results showed that 25.5 mM glucose significantly increased Ca²⁺, up-regulated the expression of Bax, P-ERK and P-JNK, and suppressed Bcl-2 expression. However, the above deleterious changes were further confirmed when co-treatment with CaSR agonist GdCl₃ (300 µM). But the effects of GdCl₃ were attenuated by 10 µM NPS-2390, a specific CaSR inhibitor. When CaSR was silence by siRNA transfection, the effects of high glucose were inhibited. These results suggest that CaSR activation could lead to the apoptosis of cardiomyocytes in diabetic cardiac injury through the induction of calcium overload, the activation of the mitochondrial, and mitogen-activated protein kinase pathway.
心脏损伤是糖尿病常伴有的一种常见病理变化。最近有证据表明，钙敏感受体（CaSR）在心脏组织中表达。然而，CaSR 在糖尿病性心脏损伤中的功能作用尚不清楚。本研究旨在探讨 CaSR 激活与糖尿病引起的心脏损伤之间的关系。体内给予链脲佐菌素（STZ）成功建立糖尿病模型，体外用 25.5mmol/L 葡萄糖模拟心肌细胞损伤。检测细胞凋亡率、细胞内钙离子浓度(Ca²⁺)、Bcl-2、Bax、细胞外信号调节蛋白激酶（ERK）、c-Jun NH₂-末端蛋白激酶（JNK）和 p38 的表达。结果显示，左心室舒张末期压（LVEDP）明显升高，左心室压力最大上升和下降速率（±dp/dtmax）以及左心室收缩压（LVSP）降低，TUNEL 染色显示心肌细胞凋亡。在体外，用流式细胞术检测 25.5mmol/L 葡萄糖诱导的乳鼠心肌细胞凋亡。进一步的结果表明，25.5mmol/L 葡萄糖显著增加Ca²⁺，上调 Bax、P-ERK 和 P-JNK 的表达，并抑制 Bcl-2 的表达。然而，当用 CaSR 激动剂 GdCl₃（300μM）共同处理时，上述有害变化进一步得到证实。但是，10μM 的 NPS-2390，一种特异性的 CaSR 抑制剂，可减弱 GdCl₃ 的作用。当用 siRNA 转染沉默 CaSR 时，高葡萄糖的作用受到抑制。这些结果表明，CaSR 激活可能通过诱导钙超载、激活线粒体和丝裂原激活蛋白激酶途径导致糖尿病性心脏损伤中的心肌细胞凋亡。
