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- Title
Protective role of ACE2-Ang-(1-7)-Mas in myocardial fibrosis by downregulating K3.1 channel via ERK1/2 pathway.
- Authors
Wang, Li-Ping; Fan, Su-Jing; Li, Shu-Min; Wang, Xiao-Jun; Gao, Jun-Ling; Yang, Xiu-Hong
- Abstract
The intermediate-conductance Ca-activated K (K3.1) 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 K3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of K3.1 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 K3.1 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 K3.1 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 K3.1 protein expression by Ang II in Tg mice, but activation of K3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2 mice, TRAM-34, the K3.1 blocker, and Ang-(1-7) inhibited increase of blood pressure, collagen deposition, and K3.1 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 K3.1 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 K3.1 channels through ERK1/2 pathway. Our results reveal that K3.1 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 K3.1 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.
- Subjects
HEART fibrosis; ANGIOTENSIN II; POTASSIUM channels; PROTEIN kinases; DOWNREGULATION; PREVENTION
- Publication
Pflügers Archiv: European Journal of Physiology, 2016, Vol 468, Issue 11/12, p2041
- ISSN
0031-6768
- Publication type
Article
- DOI
10.1007/s00424-016-1875-9