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.
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 (AT(1)) and type 2 (AT(2)) 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. AT(1) 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 AT(1) 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.
Touyz
R M
RM
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada. touyzr@ircm.qc.ca
He
G
G
Wu
X H
XH
Park
J B
JB
Mabrouk
M E
ME
Schiffrin
E L
EL
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D008875:Middle Aged; 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 / Q000503:physiopathology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
C000715470:MAS1 protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D004247:DNA; D015688:Oncogene Protein pp60(v-src); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases