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.
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