title: Protective role of ACE2-Ang-(1-7)-Mas in myocardial fibrosis by downregulating KCa3.1 channel via ERK1/2 pathway.
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.
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China. mywlpzjm@163.com.|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. mywlpzjm@163.com.
authors: Li-Ping
authors: LP
authors: Wang
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China.|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.
authors: Su-Jing
authors: SJ
authors: Fan
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China.|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.
authors: Shu-Min
authors: SM
authors: Li
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China.|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.
authors: Xiao-Jun
authors: XJ
authors: Wang
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China.|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.
authors: Jun-Ling
authors: JL
authors: Gao
authors: Department of Physiology, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei, 063000, China.|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.
authors: Xiu-Hong
authors: XH
authors: Yang
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D005355:Fibrosis; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene
keywords: ACE2-Ang-(1–7)-Mas; ERK1/2 pathway; Intermediate-conductance Ca2+-activated K+ channel; Myocardial fibrosis