Proliferation of neonatal cardiomyocytes by connexin43 knockdown via synergistic inactivation of p38 MAPK and increased expression of FGF1
Proliferation of neonatal cardiomyocytes by connexin43 knockdown via synergistic inactivation of p38 MAPK and increased expression of FGF1
复制标题
DOI：
10.1007/s00395-009-0029-z
复制
发表时间：
2009-11-01
影响因子：
9.5
通讯作者：
Kawahara, Koichi
中科院分区：
文献类型：
--
作者：
Matsuyama, Daisuke;Kawahara, Koichi
缝隙连接是细胞间连接相邻细胞质的通道。缝隙连接细胞间通讯一直被认为有助于维持组织的稳态。然而，最近的研究表明，间隙连接蛋白，间隙连接蛋白，参与调节细胞间通讯以外的多种细胞功能。尽管在新生大鼠心室肌细胞中，连接蛋白-40、-43和-45都表达，但连接蛋白43（Cx43）是主要亚型。在这项研究中，我们研究了是否以及如果是这样，如何敲低间隙连接蛋白Cx43与siRNA产生的新生心肌细胞的增殖活性的变化。Cx43-敲低导致心肌细胞增殖显著增加。为了阐明这种增加背后的机制，我们研究了是否有丝分裂原活化蛋白激酶（MAPKs）的活性改变敲低Cx43。p-p38 MAPK表达下调。此外，用p38 MAPK抑制剂处理心肌细胞显著增加了增殖活性。然后用p38 MAPK和成纤维细胞生长因子-1（FGF 1）的抑制剂共处理培养物，因为Cx43敲低也显著增加了细胞溶质FGF 1表达。与单独使用p38 MAPK抑制剂的处理相比，共同处理增强了心肌细胞的增殖。综上所述，本研究表明，Cx43敲低产生了显着增加新生心肌细胞的增殖。
Gap junctions are intercellular channels that connect the cytoplasm of adjacent cell. Gap junctional intercellular communication has long been postulated to contribute to the maintenance of tissue homeostasis. Recent studies, however, have demonstrated that connexins, gap junction proteins, are involved in the regulation of a variety of cellular functions other than intercellular communication. Although, in neonatal rat ventricular myocytes, connexin-40, -43, and -45 are all expressed, connexin43 (Cx43) is the primary subtype. In this study, we examined whether and if so how the knockdown of a gap junction protein Cx43 with siRNA produced changes in the proliferative activity of neonatal cardiomyocytes. Cx43-knockdown resulted in a significant increase in the proliferation of cardiomyocytes. To clarify the mechanisms behind this increase, we investigated whether the activity of mitogen-activated protein kinases (MAPKs) changed on knockdown of Cx43. The knockdown decreased the expression of phosphorylated p38 (p-p38) MAPK. In addition, treatment of cardiomyocytes with a p38 MAPK inhibitor significantly increased the proliferative activity. Cultures were then co-treated with an inhibitor of p38 MAPK and fibroblast growth factor-1 (FGF1), since Cx43-knockdown significantly increased cytosolic FGF1 expression as well. The co-treatment enhanced the proliferation of cardiomyocytes compared with the treatment with the p38 MAPK inhibitor alone. Taken together, the present study demonstrated that Cx43-knockdown produced a significant increase in the proliferation of neonatal cardiomyocytes.