Rabkin S W, Sunga P S, Sanghera J S, Pelech S L
Department of Medicine, University of British Columbia, Vancouver, Canada.
Cell Mol Life Sci. 1997 Dec;53(11-12):951-9. doi: 10.1007/s000180050116.
Mitogen-activated protein (MAP) kinases play a role in cell growth and are activated in the heart by cardiac stretch and various growth factors, but their role in signal transduction pathways once the heart has undergone hypertrophy is uncertain. To investigate the regulation of MAP kinases in the heart in response to angiotensin II (ang II), once cardiac hypertrophy has become established, ventricular and skeletal muscle explants were studied from Dahl S salt-sensitive and Dahl R salt-resistant rats that were on a high (6% NaCl) salt supplement in their diet. Cardiac hypertrophy was produced in the Dahl S but not R rat through NaCl-induced hypertension. MAP kinases were assayed by myelin protein phosphotransferase activity in MonoQ fractions of cell extracts. Ang II increased MAP kinases mainly in extracts from nonhypertrophic ventricles of Dahl R rats on a high-salt diet. Immunoblots revealed predominantly p44ERK1 with lower amounts p42MAPK in rat ventricle, and no apparent changes with hypertrophy. In hypertrophied hearts, ang II-induced MAP kinase activity was less markedly increased and more rapidly fell to baseline levels in comparison to the response in nonhypertrophied hearts. Prolonged ang II exposure did not produce the same effect on MAP kinase activity in ventricles from Dahl S rats on a low-salt diet, or skeletal muscle from salt-fed Dahl R and S rats. The ability of phorbol myristate acetate to simulate MAP kinase and ang II to simulate translocation of protein kinase C from the cytosole to the membrane was similarly compromised in hypertrophied ventricles. These results are consistent with a disturbance in the regulation of cell-signalling pathways in cardiac hypertrophy in which the MAP kinase response to ang II is dramatically altered.
丝裂原活化蛋白（MAP）激酶在细胞生长中发挥作用，并在心脏中因心脏牵张和各种生长因子而被激活，但其在心脏发生肥大后信号转导途径中的作用尚不确定。为了研究心脏中MAP激酶对血管紧张素II（ang II）的反应调节，在心脏肥大形成后，对饮食中添加高盐（6%氯化钠）的Dahl S盐敏感大鼠和Dahl R盐抵抗大鼠的心室和骨骼肌外植体进行了研究。通过氯化钠诱导的高血压在Dahl S大鼠而非R大鼠中产生心脏肥大。通过细胞提取物的MonoQ级分中的髓磷脂蛋白磷酸转移酶活性测定MAP激酶。Ang II主要在高盐饮食的Dahl R大鼠非肥大心室提取物中增加MAP激酶。免疫印迹显示大鼠心室中主要为p44ERK1，p42MAPK含量较低，且肥大后无明显变化。与非肥大心脏的反应相比，在肥大心脏中，ang II诱导的MAP激酶活性增加不太明显，且更快降至基线水平。长期暴露于ang II对低盐饮食的Dahl S大鼠心室或高盐喂养的Dahl R和S大鼠骨骼肌中的MAP激酶活性没有产生相同的影响。在肥大的心室中，佛波醇肉豆蔻酸酯模拟MAP激酶和ang II模拟蛋白激酶C从胞质溶胶向膜的转位的能力同样受到损害。这些结果与心脏肥大中细胞信号通路调节的紊乱一致，其中MAP激酶对ang II的反应发生了显著改变。
