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Protective role of ACE2-Ang-(1–7)-Mas in myocardial fibrosis by downregulating KCa3.1 channel via ERK1/2 pathway

  • Organ physiology
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Abstract

The intermediate-conductance Ca2+-activated K+ (KCa3.1) 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 KCa3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of KCa3.1 channel in the cardioprotective role of ACE2-Ang-(1–7)-Mas. Wild-type (WT) mice, hACE2 transgenic mice (Tg), and ACE2 deficiency mice (ACE2−/−) 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 KCa3.1 protein expression in myocardium of WT mice induced by Ang II. In Tg and ACE2−/− 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 KCa3.1 protein expression, but the changes in ACE2−/− mice were more obvious than those in Tg mice. Mas antagonist A779 reduced blood pressure, myocardium fibrosis, and myocardium KCa3.1 protein expression by Ang II in Tg mice, but activation of KCa3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2−/− mice, TRAM-34, the KCa3.1 blocker, and Ang-(1–7) inhibited increase of blood pressure, collagen deposition, and KCa3.1 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 KCa3.1 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 KCa3.1 channels through ERK1/2 pathway. Our results reveal that KCa3.1 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 KCa3.1 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.

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Acknowledgments

The work was supported by the Natural Science Foundation of Hebei Province (grant no. H2015209153) and Colleges and Universities Science and Technology Research Project of Hebei Province (grant no. QN2016003).

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Authors and Affiliations

  1. Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China

    Li-Ping Wang, Su-Jing Fan, Shu-Min Li, Xiao-Jun Wang, Jun-Ling Gao & Xiu-Hong Yang

  2. Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China

    Li-Ping Wang, Su-Jing Fan, Shu-Min Li, Xiao-Jun Wang, Jun-Ling Gao & Xiu-Hong Yang

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  1. Li-Ping Wang
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Correspondence to Li-Ping Wang.

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Experimental protocols were approved by the Institutional Animal Care and Use Committee of North China University of Science and Technology and conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, USA.

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Wang, LP., Fan, SJ., Li, SM. et al. Protective role of ACE2-Ang-(1–7)-Mas in myocardial fibrosis by downregulating KCa3.1 channel via ERK1/2 pathway. Pflugers Arch - Eur J Physiol 468, 2041–2051 (2016). https://doi.org/10.1007/s00424-016-1875-9

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  • DOI: https://doi.org/10.1007/s00424-016-1875-9

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