title: Angiotensin II upregulates K(Ca)3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts.
abstract: The proliferation of cardiac fibroblasts is implicated in the pathogenesis of myocardial remodeling and fibrosis. Intermediate-conductance calcium-activated K⁺ channels (K(Ca)3.1 channels) have important roles in cell proliferation. However, it is unknown whether angiotensin II (Ang II), a potent profibrotic molecule, would regulate K(Ca)3.1 channels in cardiac fibroblasts and participate in cell proliferation. In the present study, we investigated whether K(Ca)3.1 channels were regulated by Ang II, and how the channel activity mediated cell proliferation in cultured adult rat cardiac fibroblasts using electrophysiology and biochemical approaches. It was found that mRNA, protein, and current density of K(Ca)3.1 channels were greatly enhanced in cultured cardiac fibroblasts treated with 1 μM Ang II, and the effects were countered by the angiotensin type 1 receptor (AT₁R) blocker losartan, the p38-MAPK inhibitor SB203580, the ERK1/2 inhibitor PD98059, and the PI3K/Akt inhibitor LY294002. Ang II stimulated cell proliferation and the effect was antagonized by the K(Ca)3.1 blocker TRAM-34 and siRNA targeting K(Ca)3.1. In addition, Ang II-induced increase of K(Ca)3.1 expression was attenuated by transfection of activator protein-1 (AP-1) decoy oligodeoxynucleotides. These results demonstrate for the first time that Ang II stimulates cell proliferation mediated by upregulating K(Ca)3.1 channels via interacting with the AT₁R and activating AP-1 complex through ERK1/2, p38-MAPK and PI3K/Akt signaling pathways in cultured adult rat cardiac fibroblasts.
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: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Zhao
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Deng
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C491575:Kcnn4 protein, rat; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D044140:Receptor, Angiotensin, Type 1; C411671:TRAM 34; D018808:Transcription Factor AP-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan