MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides
MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides
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DOI：
10.1152/ajpcell.00145.2008
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发表时间：
2008-11-01
影响因子：
5.5
通讯作者：
Tallant, E. Ann
中科院分区：
文献类型：
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作者：
Gallagher, Patricia E.;Ferrario, Carlos M.;Tallant, E. Ann
Gallagher PE，Ferrario CM，Tallant EA. MAP激酶/磷酸酶途径介导血管紧张素肽对ACE 2的调节。美国生理学杂志细胞生理学295：C1169-C1174，2008年。首次发表于2008年9月3日; doi：10.1152/ajpcell.00145.2008。血管紧张素转化酶2（ACE 2）催化血管收缩剂血管紧张素II（ANG II）转化为血管舒张肽血管紧张素-（1-7）[ANG-（1-7）]。我们发现，用AT（1）受体拮抗剂奥美沙坦治疗高血压大鼠增加了胸主动脉中ACE 2 mRNA和蛋白，表明内源性ANG II张力性降低了该酶。我们现在报道，ANG II下调大鼠主动脉血管平滑肌细胞（VSMCs）中ACE 2的活性和mRNA，以减少ANG II向ANG-（1-7）的转化。虽然单独的ANG-（1-7）对ACE 2 mRNA的调节没有影响，但七肽阻止了ANG II介导的ACE 2 mRNA的降低，这种作用被选择性ANG-（1-7）受体拮抗剂[D-Ala（7）]-ANG-（1-7）阻断。ACE 2 mRNA的减少ANG II也阻止了丝裂原活化蛋白（MAP）激酶激酶抑制剂PD 98059。ANG Ⅱ处理VSMCs可增加ERK 1/ERK 2活性，而ANG-（1-7）预处理可显著降低ERK 1/ERK 2活性。ANG-（1-7）阻断ANG II介导的ACE 2 mRNA减少和MAP激酶活性增加可通过钒酸钠（一种酪氨酸磷酸酶抑制剂）或冈田酸（一种丝氨酸-苏氨酸磷酸酶抑制剂）预处理来阻止，这表明七肽激活MAP激酶磷酸酶。这项研究首次表明MAP激酶-磷酸酶途径是调节ACE 2以维持ANG II和ANG-（1-7）之间平衡的主要分子机制。ANG-（1-7）在ANG II调节ACE 2中的调节作用表明这两种肽之间存在复杂的相互作用，其由特异性受体介导以激活不同的信号传导途径。
Gallagher PE, Ferrario CM, Tallant EA. MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. Am J Physiol Cell Physiol 295: C1169-C1174, 2008. First published September 3, 2008; doi:10.1152/ajpcell.00145.2008.-Angiotensinconverting enzyme 2 (ACE2) catalyzes the conversion of the vasoconstrictor angiotensin II (ANG II) to the vasodilatory peptide angiotensin-(1-7) [ANG-(1-7)]. We showed that treatment of hypertensive rats with the AT(1) receptor antagonist olmesartan increased ACE2 mRNA and protein in the thoracic aorta, suggesting that endogenous ANG II tonically reduces the enzyme. We now report that ANG II downregulates ACE2 activity and mRNA in rat aortic vascular smooth muscle cells (VSMCs) to reduce the conversion of ANG II to ANG-(1-7). Although ANG-(1-7) alone had no effect on the regulation of ACE2 mRNA, the heptapeptide prevented the ANG II-mediated reduction in ACE2 mRNA, an effect blocked by the selective ANG-(1-7) receptor antagonist [D-Ala(7)]-ANG-(1-7). The reduction in ACE2 mRNA by ANG II was also prevented by the mitogen-activated protein ( MAP) kinase kinase inhibitor PD98059. Treatment of VSMCs with ANG II increased ERK1/ERK2 activity, which was significantly reduced by pretreatment with ANG-(1-7). Blockade of the ANG II-mediated reduction in ACE2 mRNA and increase in MAP kinase activity by ANG-(1-7) was prevented by pretreatment with sodium vanadate, a tyrosine phosphatase inhibitor, or okadaic acid, a serine-threonine phosphatase inhibitor, suggesting that the heptapeptide activates a MAP kinase phosphatase. This study is the first to show that the MAP kinase-phosphatase pathway is a primary molecular mechanism for regulating ACE2 to maintain the balance between ANG II and ANG-(1-7). The modulatory role of ANG-(1-7) in the regulation of ACE2 by ANG II suggests a complex interplay between the two peptides that is mediated by specific receptors to activate distinct signaling pathways.