Seko Yoshinori, Fujimura Tsutomu, Taka Hikari, Mineki Reiko, Murayama Kimie, Nagai Ryozo
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Biochem Biophys Res Commun. 2004 Apr 23;317(1):162-8. doi: 10.1016/j.bbrc.2004.03.021.
We previously reported that hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activated intracellular signaling such as mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated protein kinase (ERK) 1/2, p38MAPK, and stress-activated protein kinases (SAPKs). To investigate the humoral factors which mediate cardiac response to hypoxia/reoxygenation, we analyzed the conditioned media from cardiac myocytes subjected to hypoxia/reoxygenation by two-dimensional electrophoresis and mass spectrometry. We identified cyclophilin A (CyPA) as one of the proteins secreted from cardiac myocytes in response to hypoxia/reoxygenation. Hypoxia/reoxygenation induced the expression of CyPA and its cell surface receptor CD147 on cardiac myocytes in vitro. This was also confirmed by ischemia/reperfusion in vivo. Recombinant human (rh) CyPA activated ERK1/2, p38MAPK, SAPKs, and Akt in cultured cardiac myocytes. Furthermore, CyPA significantly increased Bcl-2 in cardiac myocytes. These data strongly suggested that CyPA is released from cardiac myocytes in response to hypoxia/reoxygenation and may protect cardiac myocytes from oxidative stress-induced apoptosis.
我们之前报道过，缺氧后再给氧（缺氧/复氧）会迅速激活细胞内信号传导，如丝裂原活化蛋白激酶（MAPK），包括细胞外信号调节蛋白激酶（ERK）1/2、p38MAPK和应激激活蛋白激酶（SAPK）。为了研究介导心脏对缺氧/复氧反应的体液因子，我们通过二维电泳和质谱分析了缺氧/复氧处理的心肌细胞的条件培养基。我们鉴定出亲环素A（CyPA）是心肌细胞在缺氧/复氧刺激下分泌的蛋白质之一。缺氧/复氧在体外诱导心肌细胞上CyPA及其细胞表面受体CD147的表达。这在体内的缺血/再灌注实验中也得到了证实。重组人（rh）CyPA在培养的心肌细胞中激活ERK1/2、p38MAPK、SAPK和Akt。此外，CyPA显著增加心肌细胞中的Bcl-2。这些数据强烈表明，CyPA是心肌细胞在缺氧/复氧刺激下释放的，可能保护心肌细胞免受氧化应激诱导的凋亡。
