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

• Published in: Pflügers Archiv 2016-11, Vol.468 (11-12), p.2041-2051
• Main Authors: Wang, Li-Ping, Fan, Su-Jing, Li, Shu-Min, Wang, Xiao-Jun, Gao, Jun-Ling, Yang, Xiu-Hong
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Biology; Human Physiology; Molecular Medicine; Neurosciences; Organ Physiology; Receptors
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-016-1875-9

The intermediate-conductance Ca 2+ -activated K + (K Ca 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 Ca 3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of K Ca 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 −/− ) 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 Ca 3.1 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 K Ca 3.1 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 K Ca 3.1 protein expression by Ang II in Tg mice, but activation of K Ca 3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2 −/− mice, TRAM-34, the K Ca 3.1 blocker, and Ang-(1–7) inhibited increase of blood pressure, collagen deposition, and K Ca 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 Ca 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 Ca 3.1 channels through ERK1/2 pathway. Our results reveal that K Ca 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 Ca 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.