Angiotensin II-dependent growth of vascular smooth muscle cells requires transactivation of the epidermal growth factor receptor via a cytosolic phospholipase A(2)-mediated release of arachidonic acid.
Angiotensin (Ang) II stimulates vascular smooth muscle cell (VSMC) growth via activation of cytosolic phospholipase A(2) (cPLA(2)), release of arachidonic acid (ArAc) and activation of mitogen-activated protein kinase (MAPK). The mechanism linking AT(1) receptor stimulation of ArAc release with MAPK activation may involve transactivation of the epidermal growth factor receptor (EGFR). In this study, Ang II increased phosphorylation of the EGFR and MAPK in cultured VSMC and these effects were attenuated by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)), and restored by addition of ArAc. Ang II- or ArAc-induced phosphorylation of the EGFR and MAPK were abolished by the EGFR kinase inhibitor AG1478. Ang II or ArAc also stimulated VSMC growth that was blocked by AG1478 or the MAPK kinase (MEK) inhibitor PD98059. Thus, it appears that the cPLA(2)-dependent release of ArAc may provide a mechanism for the transactivation between the AT(1) receptor and the EGFR signaling cascade.
Freeman
Ernest J
EJ
Department of Biological Sciences, Kent State University, OH 44242, USA. efreema2@kent.edu <efreema2@kent.edu>
Sheakley
Maria L
ML
Clements
Robert J
RJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D016718:Arachidonic Acid; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic