title: The role of KCa3.1 channels in cardiac fibrosis induced by pressure overload in rats.
abstract: The intermediate-conductance Ca(2+)-activated K(+) (KCa3.1) channels play a pivotal role in the proliferation and collagen secretion of cardiac fibroblasts. However, their contribution in cardiac fibrosis remains unknown. This study was designed to investigate whether KCa3.1 channels mediate the development of cardiac fibrosis. Pressure-overloaded rats were induced by abdominal aortic constriction and treated without or with KCa3.1 blocker (TRAM-34) or angiotensin type 1 receptor blocker (losartan) for 2 weeks. Besides the increase of blood pressure, angiotensin (Ang) II level in the plasma and myocardium, left ventricle mass and hydroxyproline concentration, myocardial hypertrophy, as well as significant collagen deposition in the perivascular regions and interstitium of the myocardium were observed in pressure-overloaded rats. The expression of leukocyte differentiation antigens (CD45 and CD3), macrophage surface marker (F4/80), tumor necrosis factor alpha, and monocyte chemotactic protein-1 (MCP-1) also significantly increased. All these alterations were prevented by losartan and TRAM-34. TRAM-34 also reduced the increase of renin and angiotensinogen in the plasma and myocardium of pressure-overloaded rats. Ang II promoted the migration of monocytes through endothelial cells and the secretion of MCP-1 from human umbilical vein endothelial cells in vitro, which was inhibited by TRAM-34. In conclusion, the present study demonstrates that TRAM-34 alleviates cardiac fibrosis induced by pressure overload, which is related to its inhibitory action on KCa3.1 channels and Ang II level. Our findings indicate that the inhibition of KCa3.1 channels may represent a novel approach of preventing the progression of cardiac fibrosis, and also add to the already developing literature of promising targets for TRAM-34.
authors.affiliation: Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.|Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.|Department of Physiology, School of Basic Medical Science, Hebei United University, 57 Jianshe South Road, Tangshan, 063000, Hebei, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.affiliation: Department of Pathology, Xi'an Guangren Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710004, Shaanxi, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Xiao-Zhen
authors.initials: XZ
authors.lastname: Ma
authors.affiliation: Department of Pathology, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Dang-Xia
authors.initials: DX
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China. dengxl@mail.xjtu.edu.cn.|Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China. dengxl@mail.xjtu.edu.cn.
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Deng
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000097:blood / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects; D001794:Blood Pressure; D006332:Cardiomegaly / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006909:Hydroxyproline / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; C098254:Kcnc1 protein, rat; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D051670:Shaw Potassium Channels; C411671:TRAM 34; D000808:Angiotensinogen; D012083:Renin; D019808:Losartan; D006909:Hydroxyproline
keywords: Angiotensin II; Cardiac fibrosis; Intermediate-conductance Ca2+-activated potassium channels; Migration; Monocyte