Lebeche Djamel, Hajjar Roger
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, hajjar@cvrc. mgh.harvard.edu.
J Renin Angiotensin Aldosterone Syst. 2001 Mar;2(1_suppl):S154-S161. doi: 10.1177/14703203010020012701.
The renin-angiotensin-aldosterone system (RAAS) has been identified as a major contributor to the development of cardiac hypertrophy and the subsequent transition to heart failure. G protein-coupled receptors agonists such as angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine (PE) have been implicated in hypertrophic responses in ventricular myocytes through the activation of several families of MAP kinases. In this study we examined the effect of candesartan, an Ang II type 1-(AT1)-receptor antagonist, on cardiac hypertrophy by using cultured neonatal rat cardiomyocytes. Stimulation with Ang II (100 nM), ET-1 (100 nM) or PE (1 µM) induced marked increases in [3H]Leucine incorporation (≥ 50%), compatible with enhanced protein synthesis. The addition of candesartan abrogated the increase in [3H]Leucine incorporation in response not only to Ang II but also to ET-1 and PE. To elucidate the mechanisms involved in this antihypertrophic effect of candesartan, we studied the activation of p38-MAPK, extracellular signal-regulated kinases (ERK1/2) and stress-activated protein kinases (SAPKs). Ang II, ET-1 and PE increased the phosphorylation levels of ERK1/2, p54 SAPK and p46SAPK and p38 in a time-dependent manner. This activation was completely blocked in the case of Ang II by pretreatment with candesartan. ET-1-induced activation of ERKs, SAPKs and p38 was also partially, but significantly, reduced by candesartan. PE-induced activation of SAPKs, but not ERKs and p38, was also reduced by candesartan. These results suggest that the hypertrophic response to ET-1 and PE, along with Ang II, is dependent upon a functioning AT1-receptor and may be mediated by AT 1 activation of the MAP kinases.
肾素-血管紧张素-醛固酮系统（RAAS）已被确认为导致心脏肥大并随后转变为心力衰竭的主要因素。G蛋白偶联受体激动剂，如血管紧张素II（Ang II）、内皮素-1（ET-1）和去氧肾上腺素（PE），通过激活几个丝裂原活化蛋白激酶（MAP激酶）家族，参与心室肌细胞的肥大反应。在本研究中，我们使用培养的新生大鼠心肌细胞，研究了Ang II 1型（AT1）受体拮抗剂坎地沙坦对心脏肥大的影响。用Ang II（100 nM）、ET-1（100 nM）或PE（1 µM）刺激可使[3H]亮氨酸掺入量显著增加（≥50%），这与蛋白质合成增强一致。加入坎地沙坦不仅消除了对Ang II，而且对ET-1和PE的[3H]亮氨酸掺入量的增加。为了阐明坎地沙坦这种抗肥大作用的机制，我们研究了p38-MAPK、细胞外信号调节激酶（ERK1/2）和应激激活蛋白激酶（SAPKs）的激活情况。Ang II、ET-1和PE以时间依赖性方式增加ERK1/2、p54 SAPK、p46SAPK和p38的磷酸化水平。在用坎地沙坦预处理的情况下，Ang II引起的这种激活被完全阻断。坎地沙坦也部分但显著降低了ET-1诱导的ERK、SAPK和p38的激活。坎地沙坦也降低了PE诱导的SAPK激活，但未降低ERK和p38的激活。这些结果表明，对ET-1和PE以及Ang II的肥大反应依赖于功能性AT1受体，并且可能由MAP激酶的AT1激活介导。
