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GRK2/β‐arrestin mediates arginine vasopressin‐induced cardiac fibroblast proliferation
Author(s) -
Chen Yunxuan,
Xu Feifei,
Zhang Lingling,
Wang Xiaojun,
Wang Yifan,
Woo Anthony YiuHo,
Zhu Weizhong
Publication year - 2017
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12696
Subject(s) - beta adrenergic receptor kinase , endocrinology , vasopressin , medicine , phosphorylation , biology , gene silencing , arginine , chemistry , signal transduction , microbiology and biotechnology , g protein coupled receptor , biochemistry , amino acid , gene
Summary 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 ( NRCF s) 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, MMP 9, and phosphorylated ERK 1/2 were determined by western blotting. AVP , in a time‐ and concentration‐dependent manner, promoted NRCF proliferation and the expression of MMP 2 and MMP 9. Inhibition of G protein‐coupled receptor kinase2 ( GRK 2) by the inhibitory peptide GRK 2‐Ct or knock‐down of GRK 2 suppressed AVP ‐induced BrdU incorporation and the expression of MMP 2 and α‐ SMA in NRCF s. Moreover, sh RNA ‐mediated silencing of β‐arrestin1 or β‐arrestin 2 abolished AVP ‐induced BrdU incorporation and MMP 2 expression. AVP ‐induced NRCF proliferation depended on the phosphorylation of ERK 1/2 , and inhibition of GRK 2 or silencing of β‐arrestins blocked AVP ‐induced ERK 1/2 phosphorylation. The effects of AVP on NRCF proliferation and α‐ SMA expression were blocked by SR 45059, a vasopressin receptor type1A (V 1 A R ) selective antagonist. In conclusion, AVP promotes NRCF proliferation through V 1 A R ‐mediated GRK 2/β‐arrestin/ ERK 1/2 signalling.