Protective role of ACE2-Ang-(1–7)-Mas in myocardial fibrosis by downregulating K<sub class="a-plus-plus">Casub>3.1 channel via ERK1/2 pathway

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• 作者：Li-Ping Wang ; Su-Jing Fan ; Shu-Min Li…
• 关键词：Intermediate ; conductance Ca2+ ; activated K+ channel ; ACE2 ; Ang ; (1–7) ; Mas ; ERK1/2 pathway ; Myocardial fibrosis
• 刊名：Pflügers Archiv - European Journal of Physiology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：468
• 期：11-12
• 页码：2041-2051
• 全文大小：
• 刊物主题：Human Physiology; Molecular Medicine; Neurosciences; Cell Biology; Receptors;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-2013
• 卷排序：468

文摘

The intermediate-conductance Ca2+-activated K+ (K<sub>Casub>3.1) channel plays a vital role in myocardial fibrosis induced by angiotensin (Ang) II. However, as the antagonists of Ang II, the effect of angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1–7)-Mas axis on K<sub>Casub>3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of K<sub>Casub>3.1 channel in the cardioprotective role of ACE2-Ang-(1–7)-Mas. Wild-type (WT) mice, hACE2 transgenic mice (Tg), and ACE2 deficiency mice (ACE2−/−sup>) were administrated with Ang II by osmotic mini-pumps. As the activator of ACE2, diminazene aceturate (DIZE) inhibited increase of blood pressure, collagen deposition, and K<sub>Casub>3.1 protein expression in myocardium of WT mice induced by Ang II. In Tg and ACE2−/−sup> mice, besides the elevation of blood pressure, Ang II induced transformation of cardiac fibroblast into myofibroblast and resulted in augmentation of hydroxyproline concentration and collagen deposition, as well as K<sub>Casub>3.1 protein expression, but the changes in ACE2−/−sup> mice were more obvious than those in Tg mice. Mas antagonist A779 reduced blood pressure, myocardium fibrosis, and myocardium K<sub>Casub>3.1 protein expression by Ang II in Tg mice, but activation of K<sub>Casub>3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2−/−sup> mice, TRAM-34, the K<sub>Casub>3.1 blocker, and Ang-(1–7) inhibited increase of blood pressure, collagen deposition, and K<sub>Casub>3.1 protein expression by Ang II. Moreover, DIZE and Ang-(1–7) depressed p-ERK1/2/t-ERK increases by Ang II in WT mice, and after blockage of ERK1/2 pathway with PD98059, the K<sub>Casub>3.1 protein expression was reduced in WT mice. In conclusion, the present study demonstrates that ACE2-Ang-(1–7)-Mas protects the myocardium from hypertension-induced injury, which is related to its inhibiting effect on K<sub>Casub>3.1 channels through ERK1/2 pathway. Our results reveal that K<sub>Casub>3.1 channel is likely to be a critical target on the ACE2-Ang-(1–7)-Mas axis for its protective role in myocardial fibrosis and changes of K<sub>Casub>3.1 induced by homeostasis of ACE-Ang II-AT1 axis and ACE2-Ang-(1–7)-Mas axis may be a new therapeutic target in myocardial fibrosis.