Angiotensin II stimulates mitogen-activated protein kinases and protein synthesis by a Ras-independent pathway in vascular smooth muscle cells.

Angiotensin II (ANG II), a potent hypertrophic factor of vascular smooth muscle cells (VSMC), induces activation of the ras protooncogene product (Ras) and mitogen-activated protein (MAP) kinases and subsequent stimulation of protein synthesis in VSMC. In the present study, we examined whether Ras activation is required for ANG II-induced MAP kinase activation and stimulation of protein synthesis in cultured rat VSMC. Pretreatment with tyrosine kinase inhibitors, genistein and herbimycin A, or a putative phosphatidylinositol 3-kinase inhibitor, wortmannin, completely blocked ANG II-induced Ras activation, whereas neither of them had an effect on ANG II-induced MAP kinase activation. Adenovirus-mediated expression of a dominant negative mutant of Ha-Ras completely inhibited ANG II-induced Ras activation but failed to inhibit MAP kinase activation and stimulation of protein synthesis by this vasoconstrictor. These results indicate that ANG II stimulates MAP kinases and protein synthesis by a Ras-independent pathway in VSMC.