Background
: Osteopontin (OPN), an extracellular matrix component produced by vascular smooth muscle cells (VSMC) and monocytes in response to biological stressors, is a regulator of cellular proliferation and migration. Recent studies revealed that OPN also plays a critical role in the progression of atherosclerotic plaques and that angiotensin II (AngII) is a potent upregulator of OPN expression. Therefore, the goal of the present study was to characterize the signaling mechanisms whereby AngII increases OPN expression.
Methods and Results
: YM254890, a specific inhibitor of G
q/11
, potently suppressed AngII-induced OPN expression and ERK1/2 activation. Among DN mutants of small G proteins (Ras, Rac, Rho), only DN-Ras completely suppressed AngII-induced OPN promoter activity. Dominant negative (DN)-MEK1 inhibited AngII-induced OPN promoter activity by 54%, while DN-c-Jun N-terminal kinase (JNK) or DN-p38MAP kinase had no effect. DN-Src and Csk suppressed AngII-induced OPN promoter activity by 49% and 71%, respectively. In addition, small interfering RNA against Ets-1 (a transcriptional factor downstream of ERK1/2) suppressed AngII-induced OPN expression by 54 ± 4.3%. In a separate experiment, rats were treated with the AngII type I receptor blocker, valsartan (1 mg/kg/day), or vehicle for 2 weeks after carotid artery balloon injury. The intima/media ratio and OPN expression were significantly lower in valsartan-treated rats than in vehicle-treated rats.
Conclusion
: These data suggest that AngII-induced OPN expression in VSMC is mediated by signaling cascades involving G
q/11
, the Ras-ERK axis, and c-Src, and by the transcription factor, Ets-1. Further, OPN may play a role in AngII-induced neointimal formation. These signaling molecules may represent therapeutic targets for the prevention of pathological vascular remodeling in patients with hypertension and atherosclerosis.
Angiotensin II Type I and Prostaglandin F2α Receptors Cooperatively Modulate Signaling in Vascular Smooth Muscle Cells
