Increased angiotensin II-mediated Src signaling via epidermal growth factor receptor transactivation is associated with decreased C-terminal Src kinase activity in vascular smooth muscle cells from spontaneously hypertensive rats.
We investigated whether upregulation of Src by Ang II leads to increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and whether these processes are associated with altered activation of C-terminal Src kinase (Csk), a negative regulator of Src. Furthermore, the role of epidermal growth factor receptor (EGFR) transactivation by angiotensin II (Ang II) was determined. Ang II-mediated c-Src phosphorylation was significantly greater (approximately 4-fold, P<0.01) in SHR than in Wistar-Kyoto rats (WKY). Ang II increased Csk phosphorylation 2-to 3-fold in WKY but not in SHR. Treatment of the cells with AG1478, a selective EGFR tyrosine kinase inhibitor, decreased Ang II-mediated c-Src phosphorylation, particularly in SHR. Phosphorylation of cortactin and Pyk2/focal adhesion kinase, Src-specific substrates, was increased by Ang II >3-fold, with significantly greater responses in SHR than in WKY (P<0.05). Ang II-induced ERK1/2 activation was significantly augmented (P<0.05) and sustained in VSMCs from SHR. PP2, a selective Src inhibitor, attenuated these effects and normalized the responses in SHR. Irbesartan, a selective Ang II type 1 receptor blocker, but not PD123319, a selective Ang II type 2 receptor blocker, inhibited Ang II actions. Our results demonstrate that c-Src phosphorylation and Src-dependent ERK1/2 signaling by Ang II are increased in VSMCs from SHR. These processes are associated with blunted Ang II-induced phosphorylation of Csk. EGFR transactivation contributes to Ang II-mediated Src-dependent ERK1/2 signaling. In conclusion, altered regulation of Ang II type 1 receptor-activated c-Src by Csk may be an important upstream modulator of abnormal ERK1/2 signaling in VSMCs from SHR.
Touyz
Rhian M
RM
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montreal, Canada. touyzr@ircm.qc.ca
Wu
Xiao-Hua
XH
He
Gang
G
Salomon
Steven
S
Schiffrin
Ernesto L
EL
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src); D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism
D000804:Angiotensin II; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases