K Ca 3.1 Channels Promote Cardiac Fibrosis Through Mediating Inflammation and Differentiation of Monocytes Into Myofibroblasts in Angiotensin II -Treated Rats

• Published in: Journal of the American Heart Association Vol. 8; no. 1; p. e010418
• Main Authors: She, Gang, Ren, Yu-Jie, Wang, Yan, Hou, Meng-Chen, Wang, Hui-Fang, Gou, Wei, Lai, Bao-Chang, Lei, Ting, Du, Xiao-Jun, Deng, Xiu-Ling
• Format: Journal Article
• Language: English
• Published: England 08-01-2019
• Subjects: Angiotensin II - toxicity; Animals; Blotting, Western; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis - genetics; Fibrosis - metabolism; Fibrosis - pathology; Gene Expression Regulation; Heart Ventricles - metabolism; Heart Ventricles - pathology; Immunohistochemistry; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Intermediate-Conductance Calcium-Activated Potassium Channels - biosynthesis; Intermediate-Conductance Calcium-Activated Potassium Channels - genetics; Male; Monocytes - metabolism; Monocytes - pathology; Myocardium - metabolism; Myocardium - pathology; Myofibroblasts - metabolism; Myofibroblasts - pathology; Rats; Rats, Sprague-Dawley; RNA - genetics; K‐channel; differentiation; inflammation; angiotensin II; cardiac remodeling
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.118.010418

Background Cardiac fibrosis is a core pathological process associated with heart failure. The recruitment and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. The K
3.1 channels are expressed in both ventricular fibroblasts and circulating mononuclear cells in rats and are upregulated by angiotensin II . We hypothesized that K
3.1 channels mediate the inflammatory microenvironment in the heart, promoting the infiltrated bone marrow-derived circulating mononuclear cells to differentiate into myofibroblasts, leading to myocardial fibrosis. Methods and Results We established a cardiac fibrosis model in rats by infusing angiotensin II to evaluate the impact of the specific K
3.1 channel blocker TRAM -34 on cardiac fibrosis. At the same time, mouse CD 4
T cells and rat circulating mononuclear cells were separated to investigate the underlying mechanism of the TRAM -34 anti-cardiac fibrosis effect. TRAM -34 significantly attenuated cardiac fibrosis and the inflammatory reaction and reduced the number of fibroblast precursor cells and myofibroblasts. Inhibition of K
3.1 channels suppressed angiotensin II -stimulated expression and secretion of interleukin-4 and interleukin-13 in CD 4
T cells and interleukin-4- or interleukin-13-induced differentiation of monocytes into fibrocytes. Conclusions K
3.1 channels facilitate myocardial inflammation and the differentiation of bone marrow-derived monocytes into myofibroblasts in cardiac fibrosis caused by angiotensin II infusion.