title: Ca2+-calcineurin signaling is involved in norepinephrine-induced cardiac fibroblasts activation.
abstract: Cardiac fibroblasts (CFs) activation plays a vital role in cardiac fibrosis. There are some studies demonstrate that norepinephrine (NE, an α1-adrenoceptor agonist) induced CFs proliferation. But whether Ca2+-calcineurin, a signaling concerned with growth and differentiation in various cell types, is participated in NE-induced CFs activation is unclear. In present study, we determined NE-induced CFs proliferation and differentiation, synthesis of collagen, and calcineurin (CaN) activity, and the effects of phentolamine (Phen, an α1-adrenoceptor antagonist), verapamil (Ver, a calcium channel blocker) and cyclosporine A (CsA, an inhibitor of CaN) on NE-induced CFs activation. The results showed that NE induced CFs proliferation and differentiation, increased α-SMA protein expression, increased collagen I, collagen III and fibronectin production, promoted ECM expression, activated CaN and increased CaN protein expression, which were inhibited by Phen, Ver and CsA. In vivo, more collagen deposition could be observed and total collagen volume fraction (CVF) was significantly increased in NE group. Phen, Ver and CsA decreased NE-induced collagen deposition, reduced cardiac fibrosis. Thus, our results demonstrate that Ca2+/CaN is involved in NE-induced CFs proliferation and collagen synthesis.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of The Medical College of Shihezi University Shihezi, Xinjiang 832002, China.
authors.forename: Chun-Jing
authors.initials: CJ
authors.lastname: Tian
authors.affiliation: Department of Cardiology, First Affiliated Hospital of The Medical College of Shihezi University Shihezi, Xinjiang 832002, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Pang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D019703:Calcineurin; D002118:Calcium; D009638:Norepinephrine
keywords: Calcineurin; activation; cardiac fibroblasts; norepinephrine