丝裂素活化蛋白激酶参与内皮素刺激的兔主动脉平滑肌细胞增生

内皮素（ｅｎｄｏｔｈｅｌｉｎ，ＥＴ）是已知的体内活性最强的缩血管物质，其缩血管作用由Ｇ蛋白偶联受体所介导。但ＥＴ强大的促血管平滑肌细胞（ＶＳＭＣ）增生效应的机理尚未完全阐明。本研究选用培养的兔胸主动脉ＶＳＭＣ，探讨丝裂素活化蛋白激酶（ＭＡＰＫ）在ＥＴ促细胞增生中的作用。结果表明：ＥＴ－１呈时间和浓度依赖性地促进细胞摄取￣３Ｈ－ＴｄＲ和激活ＭＡＰＫ，此作用可被蛋白激酶Ｃ（ｐｒｏｔｅｉｎｋｉｎａｓｅＣ，ＰＫＣ）抑制剂Ｓｔａｕｒｏｓｐｏｒｉｎｅ（ＳＴＰ），Ｈ－７和ＥＴ＿Ａ受体拮抗剂ＢＱ１２３所抑制，但不被酪氨酸激酶抑制剂ＨｅｒｂｉｍｙｃｉｎＡ（Ｈｅｒｂ）所抑制，用ＰＫＣ激动剂ＰＭＡ（Ｐｈｏｒｂｏｌｍｙｒｉｓｔａｔｅａｃｅｔａｔｅ）预处理ＶＳＭＣ，使其ＰＫＣ活性下调，可显著减弱ＥＴ－１对ＭＡＰＫ的激活能力。本结果提示：（１）ＭＡＰＫ参与ＥＴ－１所致的ＶＳＭＣ增生；（２）ＥＴ－１促细胞增生与激活ＭＡＰＫ的作用是由ＥＴ＿Ａ受体和ＰＫＣ介导的。

ENDOTHELIN- STIMULATED PROLIFERATION OF THORACIC ARTERY SMOOTH MUSCLE CELLS INVOLVES ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE

Endothelin (ET) is a potent vasoconstrictor whose responses are mediated through a common G-protein coupled receptor. So far little is known concerning its potential mitogenic capacity. In the present study, experiments were conducted to determine the role of mitogen-activated protein kinase (MAPK) activation in the rabbit thoracic artery smooth muscle cells (VSMC) in response to stimulation by ET-1. It was found that ET-1 produced concentration- and time-dependent increases in 3H-TdR incorporation and in MAPK activity of these cells. All the increases were inhibited by protein kinase C (PKC) inhibitors, such as Staurosporine (STP) and H-7 and by ETA receptor antagonist BQ123, but not by specific tyrosine kinase inhibitor Herbimycin A (Herb). Pretreatment with PKC activator PMA (phorbol myristate acetate) for 24 h (PKC downregulation) significantly attenuated ET-1-induced MAPK activation. These results indicate that: (1) ET-1-stimulated proliferation of VSMC involves the activation of MAPK and (2) ET-1-induced MAPK activation is mediated through ETA receptor and PKC.