title: Angiotensin-(1-7) attenuates angiotensin II-induced signalling associated with activation of a tyrosine phosphatase in Sprague-Dawley rats cardiac fibroblasts.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, The Chongqing Cardiac Arrhythmias Service Center, Chongqing, 400010, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tao
authors.forename: Jinqi
authors.initials: J
authors.lastname: Fan
authors.forename: Guoying
authors.initials: G
authors.lastname: Kao
authors.forename: Xiaoge
authors.initials: X
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Yin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zrenner
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D061251:Primary Cell Culture; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C118790:angiotensin I (1-7)
keywords: Angiotensin; Angiotensin-(1-7); Cardiac fibroblast; Extracellular signal-regulated kinase; Protein tyrosine phosphatase 1