Regulation of ACE2 in cardiac myocytes and fibroblasts
Regulation of ACE2 in cardiac myocytes and fibroblasts
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DOI：
10.1152/ajpheart.00426.2008
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发表时间：
2008-12-01
影响因子：
4.8
通讯作者：
Tallant, E. Ann
中科院分区：
文献类型：
--
作者：
Gallagher, Patricia E.;Ferrario, Carlos M.;Tallant, E. Ann
Gallagher PE，Ferrario CM，Tallant EA. ACE 2在心肌细胞和成纤维细胞中的调节。Am J Physiol Heart Circ Physiol 295：H2373-H2379，2008。首次发表于2008年10月10日; doi：10.1152/ajpheart. 00426.2008.-血管紧张素转换酶2（ACE 2）优先从ANG II形成血管紧张素-（1-7）[ANG-（1-7）]。我们发现，心脏ACE 2升高后，冠状动脉结扎大鼠与AT（1）受体阻滞剂（ARB）的治疗。从新生大鼠中分离心肌细胞和成纤维细胞，以确定ARB处理导致ACE 2上调的分子机制。ANG II显著降低心肌细胞中ACE 2活性并下调ACE 2 mRNA，ARB氯沙坦阻断了这种作用，表明ANG II调节ACE 2。ANG II还降低了心脏成纤维细胞中ACE 2 mRNA;然而，没有检测到酶活性，反映了ACE 2在这些细胞中的表达有限。内皮素-1（ET-1）也显著降低心肌细胞ACE 2 mRNA的表达。ANG II或ET-1对ACE 2 mRNA的降低可被丝裂原活化蛋白激酶激酶1抑制剂阻断，表明ANG II或ET-1激活细胞外信号调节激酶（ERK）1/ERK 2以降低ACE 2。虽然ACE 2 mRNA不受ANG-（1-7）的影响，但ANG II和ET-1介导的ACE 2 mRNA的降低均被七肽阻断。ANG-（1 -7）受体拮抗剂[D-Ala（7）]-ANG-（1- 7）可阻断ANG-（1-7）的调节作用，表明ANG-（1-7）反应是由一种特异性AT（1-7）受体介导的。用心房钠尿肽（ANP）处理心肌细胞也逆转了ANG II或ET-1对ACE 2 mRNA的下调，而单独用ANP处理无效。这些结果表明，多种肥大和抗肥大肽调节心肌细胞中ACE 2的产生，表明心脏中ACE 2的表达依赖于调节分子的补体和浓度。
Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 295: H2373-H2379, 2008. First published October 10, 2008; doi: 10.1152/ajpheart. 00426.2008.-Angiotensin-converting enzyme 2 (ACE2) preferentially forms angiotensin-(1-7) [ANG-(1-7)] from ANG II. We showed that cardiac ACE2 is elevated following treatment of coronary artery-ligated rats with AT(1) receptor blockers (ARBs). Cardiac myocytes and fibroblasts were isolated from neonatal rats to determine the molecular mechanisms for the ACE2 upregulation by ARB treatment. ANG II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, effects blocked by the ARB losartan, indicating that ANG II regulates ACE2. ANG II also reduced ACE2 mRNA in cardiac fibroblasts; however, no enzyme activity was detected, reflecting the limited expression of ACE2 in these cells. Endothelin-1 (ET-1) also significantly reduced myocyte ACE2 mRNA. The reduction in ACE2 mRNA by ANG II or ET-1 was blocked by inhibitors of mitogen-activated protein kinase kinase 1, suggesting that ANG II or ET-1 activates extracellular signal-regulated kinase (ERK) 1/ERK2 to reduce ACE2. Although ACE2 mRNA was not affected by ANG-(1-7), both the ANG II-and ET-1-mediated reductions in ACE2 mRNA were blocked by the heptapeptide. The ANG-(1-7) modulatory effect was prevented by the ANG-(1-7) receptor antagonist [D-Ala(7)]-ANG-(1-7), indicating that the ANG-(1-7) response was mediated by a specific AT(1-7) receptor. Myocyte treatment with atrial natriuretic peptide (ANP) also reversed the ACE2 mRNA downregulation by ANG II or ET-1, whereas treatment with ANP alone was ineffective. These results indicate that multiple hypertrophic and anti-hypertropic peptides regulate ACE2 production in myocytes, suggesting that ACE2 expression in the heart is dependent upon the compliment and concentration of regulatory molecules.