Regulation of Akt (protein kinase B) by nitric oxide in vascular smooth muscle cells

Growth factors induce proliferation of vascular smooth muscle cells (VSMC) presumably through activation of Akt (protein kinase B). The signaling cascade that links activated growth factor receptors to Akt is an area of active investigation, and consists of small molecular weight GTP binding proteins such as Ras as well as upstream kinases including phosphatidylinositol-4,5-bisphosphate 3-kinase (PI-3K) and phosphatidylinositol-dependent kinases (PDK1 and PDK2). Even though it is now apparent that Akt is a cell survival signal, the regulation of this kinase cascade is not clearly understood in VSMC.
Nitric oxide (NO) is a diatomic gaseous molecule known to cause vasodilation. NO is formed in the vascular tissues following activation of nitric oxide synthase (eNOS) in endothelial cells, and induction of NOS (iNOS) in VSMC. Inflammatory cytokines such as interleukin-1b, interferon-g and tumor necrosis factor-a are known to increase the expression of iNOS, and the consequent increase in NO production may result in growth arrest and/or apoptosis. The present goal of our research is to investigate whether cytokine(s)-induced production of NO leads to inhibition of Akt signaling pathway in VSMC, thereby antagonizing the mitogenic effects of growth factors. The regulatory effect of NO on Akt signaling cascade may have profound implications in understanding the mechanisms of VSMC survival in atherosclerosis and restenosis after angioplasty.

The other ongoing project is directed toward studying the regulation of vascular Akt activation under hyperinsulinemic/hyperglycemic conditions in vitro. These studies may provide an understanding of the role of Akt in the vascular complications of diabetes.