Yoshiyama M, Omura T, Takeuchi K, Kim S, Shimada K, Yamagishi H, Teragaki M, Akioka K, Iwao H, Yoshikawa J
Department of Medicine, Division of Cardiology, Osaka City University Medical School, Osaka, 545-8585, Japan.
J Mol Cell Cardiol. 2001 Apr;33(4):799-810. doi: 10.1006/jmcc.2001.1351.
Inhibition of the renin-angiotensin system has been shown to prevent left ventricular remodeling after myocardial infarction. However, the effect of angiotensin on the signal transduction pathway of left ventricular remodeling after myocardial infarction is as yet unknown. The purpose of this study was to measure myocardial MAPKs and AP-1, NF- kappa B, and Sp-1 DNA-binding activities after myocardial infarction. Moreover, we evaluated the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on signal transduction pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. Temocapril (ACE inhibitor) (3 and 30 mg/kg/day) and candesartan cilexitil (ARB) (1 and 10 mg/kg/day) were orally administered once a day. After ligation of the left descending coronary artery, JNKs (p46JNK and p55JNK) increased to 2.0- (P<0.01) and 2.8-fold (P<0.01) at 7 days, respectively. ERKs (p44ERK and p42ERK) and p38 activities did not increase significantly. AP-1 and NF- kappa B binding activities increased at 5 days, reached their peak 2.2- and 2.0-fold at 7 days. Sp-1 did not change. ACE inhibitor and ARB inhibited JNKs, NF- kappa B and AP-1 activities. Increased JNKs, AP-1, NF- kappa B, and Sp-1 DNA-binding activities were suppressed by both drugs in the infarcted region. Doppler-echocardiography showed that ACE inhibitor and ARB prevented the dilatation of left ventricular cavity at 14 days and improved diastolic filling pattern. JNKs, AP-1 and NF- kappa B activation in myocardial infarcted rats could be responsible for left ventricular remodeling after myocardial infarction and angiotensin may be related to the activation of these signals.
肾素 - 血管紧张素系统的抑制已被证明可预防心肌梗死后的左心室重构。然而，血管紧张素对心肌梗死后左心室重构信号转导通路的影响尚不清楚。本研究的目的是测量心肌梗死后心肌中的丝裂原活化蛋白激酶（MAPKs）以及活化蛋白 -1（AP -1）、核因子κB（NF -κB）和特异性蛋白 -1（Sp -1）的DNA结合活性。此外，我们评估了血管紧张素转换酶（ACE）抑制剂和血管紧张素受体阻滞剂（ARB）对信号转导通路的影响。通过结扎Wistar大鼠冠状动脉制造心肌梗死模型。替莫普利（ACE抑制剂）（3和30毫克/千克/天）和坎地沙坦酯（ARB）（1和10毫克/千克/天）每天口服给药一次。结扎左冠状动脉后，应激活化蛋白激酶（JNKs）（p46JNK和p55JNK）在第7天分别增加至2.0倍（P<0.01）和2.8倍（P<0.01）。细胞外信号调节激酶（ERKs）（p44ERK和p42ERK）以及p38活性未显著增加。AP -1和NF -κB结合活性在第5天增加，在第7天达到峰值，分别为2.2倍和2.0倍。Sp -1没有变化。ACE抑制剂和ARB抑制JNKs、NF -κB和AP -1活性。梗死区域中增加的JNKs、AP -1、NF -κB和Sp -1 DNA结合活性均被两种药物抑制。多普勒超声心动图显示，ACE抑制剂和ARB在第14天防止了左心室腔扩张，并改善了舒张期充盈模式。心肌梗死大鼠中的JNKs、AP -1和NF -κB激活可能是心肌梗死后左心室重构的原因，并且血管紧张素可能与这些信号的激活有关。
