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Vascular Smooth Muscle Cell Singnal Transduction in Vascular Remodeling

血管重塑中的血管平滑肌细胞信号转导

基本信息

批准号：
09670719
负责人：
TANIGUCHI Takahiro
金额：
$ 1.73万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

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.

血管紧张素II（Ang II）是肾素-血管紧张素系统的主要肽激素，除了在血压和循环容量的调节中发挥关键调节作用外，在各种心血管疾病的发生发展中也发挥着重要作用。尽管Ang II是细胞培养系统中VSMC的有效肥大、迁移和抗凋亡因子，但Ang II促进生长、细胞迁移和促进存活作用的分子机制尚未完全了解。我们报道了Ang II诱导多种细胞内蛋白的酪氨酸磷酸化、ras原癌基因产物(Ras)和丝裂原激活蛋白(MAP)激酶的激活以及VSMC中c-fos的表达。在本研究中，我们发现酪氨酸激酶和磷脂酰肌醇3激酶的活性是Ang II诱导的Ras激活所必需的，然而它们都不是 Ang II 刺激 MAP 激酶激活的先决条件。腺病毒介导的 Ha-Ras 显性失活突变体的表达完全抑制 ANG 11 诱导的 Ras 激活，但无法抑制 MAP 激酶激活和这种血管收缩剂对蛋白质合成的刺激。因此，Ang II 通过 VSMC 中的 Ras 独立途径刺激 MAP 激酶和蛋白质合成。此外，我们表明 Ang II 刺激酪氨酸磷酸化和两种接头蛋白的结合。 p130^<Cas> 和 c-Crk II，表明 p130^<Cas> -c-Crk II 复合物可能在 VSMC 中的 Ang II 作用中发挥作用。此外，Akt/蛋白激酶 B (PKB)（一种具有 pleckstrin 同源结构域的丝氨酸/苏氨酸激酶）也被证明会响应 Ang II 治疗而被激活。由于已知 Akt/PKB 在生长因子诱导的抗凋亡作用中发挥重要作用，因此这些结果表明 Akt/PKB 在 Ang II 的抗凋亡作用中发挥作用。因此，Ang II 激活多个信号通路，导致 Mg 11 对 VS MC 的多效性作用。