Hormonal regulation of expression and activity of the nitric oxide synthase and sodium-potassium pump in experimental models of insulin resistance, diabetes and cardiovascular disorders

Insulin-like growth factor 1 (IGF-1) and estradiol (E2) mediate relaxation in part by increasing nitric oxide synthase (NOS) gene expression and enzyme activation, and in part by activating the expression and activity of the Na+, K+-ATPase pump (sodium pump). Mechanisms by which IGF-1 and E2 exert their effects on vascular NOS and cation transport remain poorly understood in states of insulin resistance (IR), diabetes mellitus (DM) and cardiovascular disorders , as well as during normal physiological processes. These mechanisms will be addressed in this proposal. The proposed studies will focus on the effects of angiotensin II (Ang II)-, IGF-1- and E2-mediated activation of phosphatidylinositol-3-kinase (PI3K) , protein kinase B (Akt) and RhoA kinase (Rho) . We will test the hypothesis that Ang II-mediated stimulation of Rho A compromises vascular IGF-1- and E2-mediated Akt signaling and consequent NOS and sodium pump activation, which are required for vasorelaxation. This hypothesis will be tested in cultured endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) isolated from insulin-resistant, high-fat (HF) diet-fed rats; diabetic, streptozotocin-treated (STZ) rats; and hypertensive, spontaneously hypertensive rats (SHRs). The proposed studies are designed to elucidate fundamental mechanisms underlying the etiology of IR, DM and CVD-related syndromes such as hypertension.