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4686207 
Journal Article 
Angiotensin II-induced migration of vascular smooth muscle cells is mediated by p38 mitogen-activated protein kinase-activated c-Src through spleen tyrosine kinase and epidermal growth factor receptor transactivation 
Mugabe, BE; Yaghini, FA; Song, CY; Buharalioglu, CK; Waters, CM; Malik, KU 
2010 
Yes 
Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103 
J Pharmacol Exp Ther. 
332 
1 
116-124 
English 
19797620 
WOS:000272913900012 
Angiotensin II (Ang II) stimulates protein synthesis by activating spleen tyrosine kinase (Syk) and DNA synthesis through epidermal growth factor receptor (EGFR) transactivation in vascular smooth muscle cells (VSMCs). This study was conducted to determine whether Syk mediates Ang II-induced migration of aortic VSMCs using a scratch wound approach. Treatment with Ang II (200 nM) for 24 h increased VSMC migration by 1.56 +/- 0.14-fold. Ang II-induced VSMC migration and Syk phosphorylation as determined by Western blot analysis were minimized by the Syk inhibitor piceatannol (10 microM) and by transfecting VSMCs with dominant-negative but not wild-type Syk plasmid. Ang II-induced VSMC migration and Syk phosphorylation were attenuated by inhibitors of c-Src [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2)], p38 mitogen-activated protein kinase (MAPK) [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190)], and extracellular signal-regulated kinase (ERK) 1/2 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126)]. SB202190 attenuated p38 MAPK and c-Src but not ERK1/2 phosphorylation, indicating that p38 MAPK acts upstream of c-Src and Syk. The c-Src inhibitor PP2 attenuated Syk and ERK1/2 phosphorylation, suggesting that c-Src acts upstream of Syk and ERK1/2. Ang II- and epidermal growth factor (EGF)-induced VSMC migration and EGFR phosphorylation were inhibited by the EGFR blocker 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) (2 microM). Neither the Syk inhibitor piceatannol nor the dominant-negative Syk mutant altered EGF-induced cell migration or Ang II- and EGF-induced EGFR phosphorylation. The c-Src inhibitor PP2 diminished EGF-induced VSMC migration and EGFR, ERK1/2, and p38 MAPK phosphorylation. The ERK1/2 inhibitor U0126 (10 microM) attenuated EGF-induced cell migration and ERK1/2 but not EGFR phosphorylation. These data suggest that Ang II stimulates VSMC migration via p38 MAPK-activated c-Src through Syk and via EGFR transactivation through ERK1/2 and partly through p38 MAPK. 
Angiotensin II/pharmacology/physiology; Animals; Aorta, Thoracic/cytology; Butadienes/pharmacology; Cell Culture Techniques; Cell Migration Assays; Cell Movement/drug effects; Cells, Cultured; Enzyme Inhibitors/pharmacology; Epidermal Growth Factor/antagonists & inhibitors/genetics; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism; Muscle, Smooth, Vascular/cytology/drug effects/enzymology/metabolism; Nitriles/pharmacology; Phosphorylation; Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism; Quinazolines; Rats, Sprague-Dawley; Syk Kinase; Transcriptional Activation/drug effects; Tyrphostins/pharmacology; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism; src-Family Kinases; 11128-99-7; 170449-18-0; 62229-50-9