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Angiotensin‐(1–7) attenuates angiotensin II‐induced signalling associated with activation of a tyrosine phosphatase in Sprague–Dawley rats cardiac fibroblasts
Author(s) -
Tao Xiaoling,
Fan Jinqi,
Kao Guoying,
Zhang Xiaoge,
Su Li,
Yin Yuehui,
Zrenner Bernhard
Publication year - 2014
Publication title -
biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 85
eISSN - 1768-322X
pISSN - 0248-4900
DOI - 10.1111/boc.201400015
Subject(s) - biology , angiotensin ii , protein tyrosine phosphatase , endocrinology , medicine , signalling , renin–angiotensin system , phosphatase , tyrosine , microbiology and biotechnology , phosphorylation , biochemistry , blood pressure
Background information Angiotensin‐(1–7) [ANG‐(1–7)] mediates vasodilation, antiproliferation, anti‐apoptosis and antifibrosis, therefore, it opposes the effects of angiotensin II (ANG II). However, the detailed signal transduction mechanism following the Mas receptor activated by ANG‐(1–7) is still poorly understood. Src homology2‐containing inositol phosphatase 1 (SHP‐1), a redoxsensitive protein tyrosine phosphatase, negatively influences downstream signalling molecules, such as mitogen‐activated protein kinases (MAPKs), through dephosphorylation, thereby inhibiting proliferative and profibrotic signalling induced by ANG II. Therefore, we hypothesised that SHP‐1 may mediate the antiproliferative signalling of ANG‐(1–7) through the regulation of the dynamic balance of MAPKs and SHP‐1 in isolated cardiac fibroblasts. Primary culture of neonatal Sprague–Dawley rats cardiac fibroblasts was treated separately with different interventions to investigate this issue. Results Our data revealed that ANG II increased the phosphorylation of extracellular signal‐related kinase (p‐ERK1/2) and the ratio of (p‐ERK1/2)/(ERK1/2), but ANG‐(1–7) decreased them. The effects of ANG‐(1–7) on the phosphorylation p‐ERK1/2 were blocked by the Mas receptor antagonist A‐779. Unlike ANG II, which decreased the activity of SHP‐1, ANG‐(1–7) increased its activity. Overexpression of SHP‐1 attenuated the ANG II‐stimulated phosphorylation of c‐Src, its downstream molecules ERK1/2, α‐smooth muscle actin and transforming growth factor‐β1 (TGF‐β1). These effects were also inhibited by the specific inhibitor of SHP‐1, sodium stibogluconate. ANG‐(1–7) had no significant effects on the gene expression of TGF‐β1, collagen I or collagen III, but was found to antagonise the stimulatory effects of ANG II on them. Conclusions ANG‐(1–7), through Mas receptor, activates SHP‐1 in cardiac fibroblasts, which can negatively modulate ANG II‐induced phosphorylation of c‐Src and MAPKs, and inhibits profibrotic factors TGF‐β1 and collagen production. ANG‐(1–7) can thereby serve as a protective role by counteracting the effects of ANG II.