title: Transient receptor potential melastatin 7 (TRPM7) contributes to H2O2-induced cardiac fibrosis via mediating Ca(2+) influx and extracellular signal-regulated kinase 1/2 (ERK1/2) activation in cardiac fibroblasts.
abstract: Transient receptor potential melastatin 7 (TRPM7), a Ca(2+)-nonselective cation channel, plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in hydrogen peroxide (H2O2)-induced cardiac fibrosis remains unclear. This study aimed to explore whether TRPM7 channels are involved in H2O2-induced cardiac fibrosis and the underlying mechanisms. Our results showed that 2-aminoethoxydiphenylborate (2-APB), which is commonly used to block TRPM7 channels, inhibited H2O2-induced cardiac fibrosis via attenuating the overexpression of important fibrogenic biomarkers and growth factors in cardiac fibroblasts, including collagen type I (Col I), fibronectin (FN), smooth muscle α-actin (α-SMA), connective tissue growth factor (CTGF), and transforming growth factor-β1 (TGF-β1). In addition, 2-APB also decreased H2O2-mediated elevation of the concentration of intracellular Ca(2+) ([Ca(2+)]i). Meanwhile, silencing TRPM7 channels by shRNA interference also impaired the increased [Ca(2+)]i and upregulation of Col I, FN, α-SMA, CTGF, and TGF-β1 induced by H2O2. Furthermore, we found that H2O2-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) decreased in TRPM7-shRNA cells and Ca(2+)-free culture media. These results demonstrated that TRPM7 channels contributed to H2O2-induced cardiac fibrosis and suggested that this contribution may be through mediating Ca(2+) influx and phosphorylation of ERK1/2.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, China.
authors.forename: Jin-Lei
authors.initials: JL
authors.lastname: Guo
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Jia
authors.forename: Yun-Zi
authors.initials: YZ
authors.lastname: Ma
authors.forename: Bo-Yu
authors.initials: BY
authors.lastname: Zhang
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Jiang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006861:Hydrogen Peroxide / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D017207:Rats, Sprague-Dawley; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D002118:Calcium; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D005353:Fibronectins; D006861:Hydrogen Peroxide; D048052:Mitogen-Activated Protein Kinase 3; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D016212:Transforming Growth Factor beta; C526316:CCN2 protein, rat; C498862:Acta2 protein, rat; C486584:Trpm7 protein, rat