(Hypertension. 2001;38:56.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Src Is an Important Mediator of Extracellular Signal–Regulated Kinase 1/2–Dependent Growth Signaling by Angiotensin II in Smooth Muscle Cells From Resistance Arteries of Hypertensive Patients
From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal (R.M.T., G.H., X.-H.W., M.E.M., E.L.S.), Montreal, Quebec, Canada; and Samsung Cheil Hospital, Sungkyunkwan University School of Medicine (J.B.P.), Seoul, Korea.
Reprint requests to Rhian M. Touyz, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, Canada H2W 1R7. E-mail touyzr{at}ircm.qc.ca
Abstract— The role of c-Src in growth signaling by angiotensin (Ang) II was investigated in vascular smooth muscle cells (VSMCs) from arteries of hypertensive patients. c-Src and extracellular signal–regulated kinase 1/2 (ERK1/2) activity, proto-oncogene expression, activating protein-1 (AP-1) DNA-binding activity, and DNA and protein synthesis were studied in Ang II–stimulated VSMCs derived from small peripheral resistance arteries of normotensive subjects (NTs, n=5) and age-matched untreated hypertensive patients (HTs, n=10). Ang II type 1 (AT1) and type 2 (AT2) receptor status was also assessed. Ang II dose-dependently increased the synthesis of DNA and protein, with enhanced effects in VSMCs from HTs. PD 098,059, a selective inhibitor of the ERK1/2 pathway, attenuated Ang II–stimulated growth in HTs. The effects of PD 098,059 were greater in HTs than in NTs. In NTs, Ang II transiently increased ERK1/2 phosphorylation, whereas in HTs, Ang II–stimulated actions were augmented and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 activity and normalized ERK1/2 responses in HTs. Ang II–induced c-Src phosphorylation was 2- to 3-fold greater in HTs than in NTs. In HTs but not NTs, kinase activation was followed by overexpression of c-fos and enhanced AP-1 DNA-binding activity. PD 098,059 and PP2 attenuated these responses. AT1 receptor expression was similar in NTs and HTs. In HT cells transfected with c-fos antisense oligodeoxynucleotide, Ang II–stimulated growth was reduced compared with sense oligodeoxynucleotide. Our findings suggest that augmented Ang II–stimulated VSMC growth is mediated via hyperactivation of c-Src–regulated ERK1/2-dependent pathways, leading to overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. Because AT1 receptor expression was unaltered in HTs, increased Ang II signaling may be a postreceptor phenomenon. These data define a signal transduction pathway whereby Ang II mediates exaggerated growth in VSMCs from HTs.
Key Words: receptors, angiotensin • signal transduction • arteries, resistance • hypertension, essential
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