The role of KCa3.1 channels in cardiac fibrosis induced by pressure overload in rats.
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.
['Zhao|Li-Mei|LM|', 'Wang|Li-Ping|LP|', 'Wang|Hui-Fang|HF|', 'Ma|Xiao-Zhen|XZ|', 'Zhou|Dang-Xia|DX|', 'Deng|Xiu-Ling|XL|']
D047228:Angiotensin II Type 1 Receptor Blockers D000808:Angiotensinogen D000818:Animals D001012:Aorta, Abdominal D001794:Blood Pressure D006332:Cardiomegaly D016207:Cytokines D005355:Fibrosis D006909:Hydroxyproline D019808:Losartan D008297:Male D009206:Myocardium D026902:Potassium Channel Blockers D011720:Pyrazoles D051381:Rats D017207:Rats, Sprague-Dawley D012083:Renin D051670:Shaw Potassium Channels
Cardiac fibrosis Monocyte Migration Angiotensin II Intermediate-conductance Ca2+-activated potassium channels