Tang Jiebing, Wang Guixiang, Liu Yue, Fu Yu, Chi Jinyu, Zhu Yejing, Zhao Yanru, Yin Xinhua
Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Pharmazie. 2011 Jan;66(1):52-7.
The aim of this study was to investigate whether Cyclosporin-A (CsA)-induced myocardial injury is mediated by elevating the intracellular calcium concentration ([Ca2+]i) through the Calcium sensing receptor (CaSR). Cultured neonatal rat cardiomyocytes were treated with CsA, with or without pretreatment with the CaSR-specific antagonist NPS2390 or the CaSR-specific agonist gadolinium chloride (GdCI3). At 2 h, 4 h, 6 h and 8 h after CsA treatment, the ultrastructural changes of the cardiomyocytes were observed. In addition, the lactate dehydrogenase (LDH) and creatine kinase (CK) release from the cardiomyocytes, the [Ca2+]i and the level of CaSR expression were determined. With increasing time of CsA treatment, ultrastructural damage of cardimyocytes gradually aggrevated, LDH and CK release and [Ca2+]i also gradually increased. CaSR mRNA and protein expression increased at 4 h after CsA treatment. Compared with CsA treatment alone, pretreatment with NPS2390 lessened the ultrastructural damage of the cardiomyocytes as well as decreased the LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. Conversely, pretreatment with GdCI3 aggravated the ultrastructural damage of the cardiomyocytes as well as increased LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. These results demonstrate that CsA induced cardiomyocyte injury in a time-dependent manner. Moreover, CsA-induced cardiomyocyte injury was related to CaSR-mediated intracellular calcium overload. These findings provide new insight into the mechanisms involved in CsA-induced myocardial injury.
本研究的目的是调查环孢素A（CsA）诱导的心肌损伤是否通过钙敏感受体（CaSR）升高细胞内钙浓度（[Ca2+]i）介导。用CsA处理培养的新生大鼠心肌细胞，同时或不预先用CaSR特异性拮抗剂NPS2390或CaSR特异性激动剂氯化钆（GdCI3）处理。在CsA处理后2小时、4小时、6小时和8小时，观察心肌细胞的超微结构变化。此外，测定心肌细胞中乳酸脱氢酶（LDH）和肌酸激酶（CK）的释放、[Ca2+]i以及CaSR表达水平。随着CsA处理时间的增加，心肌细胞的超微结构损伤逐渐加重，LDH和CK释放以及[Ca2+]i也逐渐增加。CsA处理后4小时CaSR mRNA和蛋白表达增加。与单独使用CsA处理相比，用NPS2390预处理减轻了心肌细胞的超微结构损伤，并降低了LDH和CK释放、[Ca2+]i以及CaSR mRNA和蛋白的表达。相反，用GdCI3预处理加重了心肌细胞的超微结构损伤，并增加了LDH和CK释放、[Ca2+]i以及CaSR mRNA和蛋白的表达。这些结果表明，CsA以时间依赖性方式诱导心肌细胞损伤。此外，CsA诱导的心肌细胞损伤与CaSR介导的细胞内钙超载有关。这些发现为CsA诱导心肌损伤的机制提供了新的见解。
