Angiotensin II-induced osteopontin expression in vascular smooth muscle cells involves Gq/11, Ras, ERK, Src and Ets-1.
Recent studies suggest that osteopontin (OPN) plays a critical role in the progression of atherosclerotic plaques and that angiotensin II (Ang II) is a potent upregulator of OPN expression. The goal of the present study was to characterize the signaling mechanisms whereby Ang II increases OPN expression in vascular smooth muscle cells (VSMC). YM-254890, a specific inhibitor of G(q/11), potently suppressed Ang II-induced OPN expression and ERK1/2 activation. Among dominant-negative (DN) mutants of small G proteins, only DN-Ras suppressed Ang II-induced OPN promoter activity. DN-MEK1 markedly inhibited Ang II-induced OPN promoter activity, while neither DN-JNK nor DN-p38 MAP kinase had any effect. DN-Src and DN-Fyn suppressed Ang II-induced OPN promoter activity. YM-254890 inhibited Ang II-induced Src and Ras activation, and PP2, a selective inhibitor for the Src kinase family, inhibited Ras activation, suggesting that the G(q/11)-Src-Ras axis is the upstream signaling cascade for Ang II-induced OPN expression. Finally, small interfering RNA against Ets-1 suppressed Ang II-induced OPN expression. In conclusion, these data suggest that Ang II-induced OPN expression in VSMC is mediated by signaling cascades involving G(q/11) the Ras-ERK axis, and the Src kinase family, and by the transcription factor, Ets-1. These signaling molecules may represent therapeutic targets for the prevention of pathological vascular remodeling.
Abe
Keiko
K
Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Nakashima
Hidekatsu
H
Ishida
Mari
M
Miho
Narimasa
N
Sawano
Mariko
M
Soe
Nwe Nwe
NN
Kurabayashi
Masahiko
M
Chayama
Kazuaki
K
Yoshizumi
Masao
M
Ishida
Takafumi
T
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002404:Catheterization / Q000009:adverse effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases
C494043:Ets1 protein, rat; D010456:Peptides, Cyclic; D050784:Proto-Oncogene Protein c-ets-1; C475455:YM-254890; D053495:Osteopontin; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D018631:ras Proteins