Hayashida W, Kihara Y, Yasaka A, Inagaki K, Iwanaga Y, Sasayama S
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
J Mol Cell Cardiol. 2001 Apr;33(4):733-44. doi: 10.1006/jmcc.2001.1341.
Mitogen-activated protein kinases (MAPKs) are involved in the early development of cardiac hypertrophy, but their roles in chronic left ventricular hypertrophy (LVH) are unclear. We studied the angiotensin (Ang) II-induced cardiac MAPK activation of the hypertensive Dahl salt-sensitive (DS) rats in the subacute developing LVH stage, the chronic compensated LVH stage, and the congestive heart failure (CHF) stage. In the isolated, coronary-perfused heart preparation, Ang II infusion (1x10(-6)mol/l) activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38-MAPK in the LV myocardium. No substantial differences were observed in the Ang II-induced ERK activation between the normotensive control DS rats and the hypertensive DS rats in either stage. In contrast, the Ang II-induced activation of JNK and p38-MAPK was augmented in the subacute LVH stage of the hypertensive DS rats, but then progressively attenuated in the chronic LVH and CHF stages. Chronic treatment with an angiotensin converting enzyme inhibitor, temocapril (20 mg/kg/day), ameliorated the responsiveness of the JNK/p38-MAPK activation, suggesting that the decreased JNK/p38-MAPK activation is a consequence of negative feedback regulation for the activated cardiac renin-angiotensin system in chronic LVH and CHF. Thus, the Ang II-induced activation of multiple cardiac MAPK pathways are differentially regulated, depending on the stages of chronic hypertrophic process. The JNK and p38-MAPK activation may be involved in the early development of adaptive LVH. However, the responsiveness of the cardiac JNK/p38-MAPK pathways progressively decreased in chronic LVH and CHF under the chronic activation of tissue renin-angiotensin system.
丝裂原活化蛋白激酶（MAPKs）参与心脏肥大的早期发展，但其在慢性左心室肥大（LVH）中的作用尚不清楚。我们研究了在高血压Dahl盐敏感（DS）大鼠亚急性左心室肥厚发展阶段、慢性代偿性左心室肥厚阶段和充血性心力衰竭（CHF）阶段，血管紧张素（Ang）II诱导的心脏MAPK激活情况。在离体冠状动脉灌注心脏标本中，输注Ang II（1×10⁻⁶mol/L）可激活左心室心肌中的细胞外信号调节激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38-MAPK。在任何一个阶段，正常血压对照DS大鼠和高血压DS大鼠之间，Ang II诱导的ERK激活均未观察到显著差异。相反，在高血压DS大鼠的亚急性左心室肥厚阶段，Ang II诱导的JNK和p38-MAPK激活增强，但在慢性左心室肥厚和CHF阶段逐渐减弱。用血管紧张素转换酶抑制剂替莫卡普利（20mg/kg/天）进行慢性治疗，可改善JNK/p38-MAPK激活的反应性，这表明JNK/p38-MAPK激活的降低是慢性左心室肥厚和CHF中激活的心脏肾素-血管紧张素系统负反馈调节的结果。因此，Ang II诱导的多种心脏MAPK途径的激活受到不同调节，这取决于慢性肥厚过程的阶段。JNK和p38-MAPK激活可能参与适应性左心室肥厚的早期发展。然而，在组织肾素-血管紧张素系统的慢性激活下，慢性左心室肥厚和CHF中心脏JNK/p38-MAPK途径的反应性逐渐降低。
