|Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
Angiotensin II (Ang II), the main peptide hormone of the renin-angiotensin system, has been known to play an important role in the development of various cardiovascular diseases in addition to its key regulatory role in the regulation of blood pressure and circulating volume. Although Ang II is a potent hypertrophic, migratory and anti-apoptotic factor of VSMC in a cell culture system, molecular mechanisms responsible for growth promoting, cell migrating and survival promoting actions of Ang II have not been fully understood. We have reported that Ang II induces tyrosine phosphorylation of multiple intracellular proteins, activation of the ras protooncogene product (Ras) and mitogen-activated protein (MAP) kinases and expression of c-fos in VSMC.In the present research, we revealed that activities of tyrosine kinase(s) and phosphatidylinositol 3-kinase are required for Ang II-induced Ras activation, whereas neither of them is not prerequisite for Ang II-stimulated MAP kinase activation. Adenovirus-mediated expression of a dominant negative mutant of Ha-Ras completely inhibited ANG 11-induced Ras activation, but failed to inhibit MAP kinase activation and stimulation of protein synthesis by this vasoconstrictor. Thus, Ang II stimulates MAP kinases and protein synthesis by a Ras-independent pathway in VSMC.Further, we showed that Ang II stimulates tyrosine phosphorylation and association of two adapter proteins, . p130^<Cas> and c-Crk II, proposing that p130^<Cas> -c-Crk II complex could play a role in Ang II action in VSMC.Moreover, Akt/protein kinase B (PKB), a serine/threonine kinase with a pleckstrin homology domain, is also shown to be activated in response to Ang II treatment. Since Akt/PKB is known to play an important role in growth factor-induced anti-apoptotic effect, these results suggested a role of Akt/PKB in anti-apoptotic effect of Ang II.Thus, Ang II activates multiple signaling pathways, resulting pleiotropic effects of Mg 11 on VS MC.