Ohkawa Yasuyuki, Hayashi Ken'ichiro, Sobue Kenji
Department of Neuroscience, Osaka University Graduate School of Medicine (D13), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2003 Jan 31;301(1):78-83. doi: 10.1016/s0006-291x(02)02965-0.
The calcineurin-mediated pathway is involved in skeletal and cardiac hypertrophy and vascular development in vivo, but the relationship between this pathway and the phenotype of smooth muscle cells (SMCs) remains unknown. Using visceral SMCs in culture as a model system of differentiated SMCs, we investigated the role of the calcineurin-mediated pathway in maintaining the differentiated phenotype of SMCs, which depends on the insulin-like growth factor (IGF-I)-triggered activation of the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB(Akt)) pathway. Treatment with calcineurin inhibitors, cyclosporin A or FK506, or the forced expression of the natural calcineurin inhibitor, CAIN, induced SMC dedifferentiation. Notably, suppression of the promoter activities of the SMC molecular markers caldesmon and alpha1 integrin by blocking the PI3-K/PKB(Akt) pathway was rescued by the forced expression of constitutively active calcineurin Aalpha, suggesting that the calcineurin-mediated pathway is critical for maintaining the differentiated phenotype of SMCs and works downstream of the PI3-K/PKB(Akt) pathway.
钙调神经磷酸酶介导的信号通路参与体内骨骼和心脏肥大以及血管发育，但该信号通路与平滑肌细胞（SMC）表型之间的关系仍不清楚。我们以培养的内脏SMC作为分化型SMC的模型系统，研究了钙调神经磷酸酶介导的信号通路在维持SMC分化表型中的作用，该表型依赖于胰岛素样生长因子（IGF-I）触发的磷脂酰肌醇3-激酶（PI3-K）/蛋白激酶B（PKB(Akt)）信号通路的激活。用钙调神经磷酸酶抑制剂环孢素A或FK506处理，或强制表达天然钙调神经磷酸酶抑制剂CAIN，均可诱导SMC去分化。值得注意的是，通过强制表达组成型活性钙调神经磷酸酶Aα可挽救因阻断PI3-K/PKB(Akt)信号通路而导致的SMC分子标记物钙调蛋白和α1整合素启动子活性的抑制，这表明钙调神经磷酸酶介导的信号通路对于维持SMC的分化表型至关重要，且在PI3-K/PKB(Akt)信号通路的下游发挥作用。
