ANG II AND IGF-1 INTERACTION IN CARDIOVASCULAR TISSUE

描述（改编自研究者摘要）：血管紧张素II（Ang II）和 胰岛素样生长因子-1（IGF-1），两种由胰岛素样生长因子产生的多效肽， 心脏和脉管系统以自分泌/旁分泌方式在这些细胞上起作用， 具有相互血液动力学效应的组织。IGF-1增加心肌细胞 收缩性与细胞内钙[Ca 2 +]I的增加平行， 而在血管系统中，这种肽通过增加血管内皮细胞的活性来介导扩张。 一氧化氮（NO）（即，一氧化氮合酶[NOS]基因表达和NOS酶 激活）和阳离子转运（Na+，K+-ATP酶基因表达和泵 活动）。最近的报告表明，IGF-1通过一个 磷脂酰肌醇3-激酶（PI 3-激酶）途径增加心肌细胞 肌丝-Ca 2+敏感性，从而增强收缩力并减弱血管 收缩通过这条途径。此外，在组织胰岛素和 IGF-1抵抗、PI 3-激酶介导的心脏和血管效应是 明显减弱。 大量数据表明，血管紧张素II有助于降低胰岛素 心脏组织和血管平滑肌细胞中PI 3-激酶刺激 （VSMC）。因此，他们认为，在以下方面存在着关键的平衡： 血管紧张素II和胰岛素样生长因子-1通过PI 3-激酶途径介导的心血管作用 调变因此，在心血管肾素血管紧张素系统状态下， (RAS)过度表达和IGF-1抗性，IGF-1增加的能力， PI 3激酶依赖的心肌细胞钙敏感性和VSMC NOS/Na+，K+-ATP酶 基因表达和活性被破坏。他们预计， 组织Ang II过量和IGF-1抗性影响相似，但 显著低于通过PI 3-激酶的分子敲除产生的 通路为了检查心脏和VSMC Ang II过量的影响，他们 将在体外研究这些细胞中Ang II和IGF-1的相互作用， 从RAS组织过表达的两种体内模型中分离的细胞： Ren-2d和两肾一夹大鼠。探讨胰岛素样生长因子-1抵抗的作用 在两种肽的相互作用中，它们将利用胰岛素和IGF-1 耐药Zucker肥胖大鼠为了阻断PI 3激酶通路， 将使用腺病毒和FuGENE转染显性阴性p85构建体 方法分别在VSMC和新生心肌细胞中进行。因此 建议的研究将探讨PI 3-激酶在介导 血管紧张素II/IGF-1的心血管相互作用后，短期在体外血管紧张素 II暴露和长期体内Ang II组织过量。

DESCRIPTION (Adapted from Investigator's Abstract): Angiotensin II (Ang II) and insulin-like growth factor-1 (IGF-1), two pleiotropic peptides produced by the heart and vasculature, function in an autocrine/paracrine fashion on these tissues with reciprocal hemodynamic effects. IGF-1 increases cardiomyocyte contractility in parallel with increases in intracellular calcium [Ca2+]I, whereas in the vasculature, this peptide mediates dilation through increases in nitric oxide (NO)(i.e., NO synthase [NOS] gene expression and NOS enzyme activation) and cation transport (Na+, K+-ATPase gene expression and pump activity). Recent reports indicate that IGF-1 works through a phosphatidylinositol 3-kinase (PI3-kinase) pathway to increase cardiomyocyte myofilament-Ca2+ sensitivity and thus contractility and attenuates vascular contraction through this pathway. Moreover, in states of tissue insulin and IGF-1 resistance, PI3-kinase mediated cardiac and vascular effects are significantly attenuated. Substantive data suggest that Ang II contributes to decreased insulin stimulation of PI3-kinase in cardiac tissue and vascular smooth muscle cells (VSMC). Accordingly, they propose that there exists a critical balance between the cardiovascular actions of Ang II and IGF-1 mediated via PI3-kinase pathway modulation. Therefore, in states of cardiovascular renin angiotensin system (RAS) over expression and IGF-1 resistance, the ability of IGF-1 to increase PI3-kinase dependent cardiomyocyte-Ca2+ sensitivity and VSMC NOS/Na+, K+-ATPase gene expression and activity is disrupted. They anticipate that the relative impact of tissue Ang II excess and IGF-1 resistance will be similar, but significantly less than that produced by molecular knockout of the PI3-kinase pathway. In order to examine the impact of heart and VSMC Ang II excess, they will study Ang II and IGF-1 interactions in these cells in vitro, as well as in cells isolated from two in vivo models of RAS tissue over expression: the Ren-2d and the two kidney one-clip rat. To explore the role of IGF-1 resistance in interaction of the two peptides they will employ the insulin and IGF-1 resistant Zucker obese rat. In order to interrupt the PI3-kinase pathway, they will transfect a dominant-negative p85 construct using adenovirus and FuGENE methodologies in VSMC and neonatal cardiomyocytes, respectively. Thus, the proposed investigation will explore the role of PI3-kinase in mediating the cardiovascular interactions of AngII/IGF-1 after both short-term in vitro Ang II exposure and longer-term in vivo Ang II tissue excess.