title: GRK2/β-arrestin mediates arginine vasopressin-induced cardiac fibroblast proliferation.
abstract: Cardiac fibrosis is a pathological feature commonly found in hearts exposed to haemodynamic orneurohormonal stress. Elevated levels of arginine vasopressin (AVP) are closely associated with the progression of heart failure and could be an underlying cause of cardiac fibrosis. The aim of this study is to characterize the effect of AVP on neonatal rat cardiac fibroblasts (NRCFs) and to illustrate its signalling mechanism. The proliferative effect of AVP was assessed by methylthiazolyldiphenyl-tetrazolium assay and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and the amounts of cellular signalling proteins α-smooth muscle actin (α-SMA), matrix metalloproteinase (MMP) 2, MMP9, and phosphorylated ERK1/2were determined by western blotting. AVP, in a time- and concentration-dependent manner, promoted NRCF proliferation and the expression of MMP2 and MMP9. Inhibition of G protein-coupled receptor kinase2 (GRK2) by the inhibitory peptide GRK2-Ct or knock-down of GRK2 suppressed AVP-induced BrdU incorporation and the expression of MMP2 and α-SMA in NRCFs. Moreover, shRNA-mediated silencing of β-arrestin1 or β-arrestin 2 abolished AVP-induced BrdU incorporation and MMP2 expression. AVP-induced NRCF proliferation depended on the phosphorylation of ERK1/2, and inhibition of GRK2 or silencing of β-arrestins blocked AVP-induced ERK1/2phosphorylation. The effects of AVP on NRCF proliferation and α-SMA expression were blocked by SR45059, a vasopressin receptor type1A (V1AR) selective antagonist. In conclusion, AVP promotes NRCF proliferation through V1AR-mediated GRK2/β-arrestin/ERK1/2signalling.
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Yunxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Anthony Yiu-Ho
authors.initials: AY
authors.lastname: Woo
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, China.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000494:pharmacology*; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D013997:Time Factors; D000071557:beta-Arrestins / Q000378:metabolism*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins; D001127:Arginine Vasopressin; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: 
  ERK
  1/2
  ; GRK2; MMP-2; MMP-9; arginine vasopressin; cardiac fibroblasts; proliferation; rat; α-smooth muscle actin; β-arrestin 1; β-arrestin 2