Regulation of Rho Signaling by S-Nitrosothiols

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): Small GTP binding proteins of the ras superfamily are recognized to play a key role in development of cardiovascular disease. In this regard Rho proteins are particularly important. For example RhoA signaling through Rho-kinases regulate diverse vascular functions including smooth muscle contraction and migration, leukocyte-endothelial cell interactions, tissue factor expression, cell differentiation and cell proliferation. The Rho pathway is activated by vasoactive agonist including angiotensin II, endothelin I, thrombin, thromboxane A2, etc., whose over-activity is commonly associated with cardiovascular disease and contributes to systemic and pulmonary hypertension, vascular inflammation, and atherosclerosis. Rho pathway activation can be seen early in development of hypertension and Rho-kinase inhibitors relax vascular tissues, reduce blood pressure and inhibit smooth muscle proliferation and vascular remodeling. In contrast to RhoA activation, derivatives of nitric oxide (NO) reduce blood pressure, inhibit thrombogenesis, inhibit smooth muscle proliferation and generally play an anti-atherogenic role. S-nitrosothiols occurring in the circulation may be particularly important for these effects. Interactions between the RhoA pathway and NO production have recently emerged with the demonstration that decreased NO synthesis leads to increased RhoA signaling. While the mechanisms for this effect is not known, we have recently found that S-nitrosothiols derived from NO, oxidize and reversibly inhibit GDP-GTP exchange in purified RhoA protein, inhibit translocation of RhoA to the membrane and block modification of downstream targets of Rho-kinase. The potential implication of these findings is that NO-derivatives such as S-nitrosothiols oppose mechanisms dependent on RhoA/Rho-kinase activation. Thus our hypothesis is that S-nitrosothiols negatively regulate Rho signaling protecting the vasculature from pro-atherogenic mechanisms. We will investigate this hypothesis using molecular, cellular and animal models. Data gathered from these studies will have important implications and suggest new mechanisms through which nitric oxide regulates vascular function. In addition, pharmacologic approaches based on S-nitrosothiols are feasible and may lead to new therapies which may include acute treatment of hypertensive disorders and chronic treatment of complications associated with atherosclerosis. PUBLIC HEALTH RELEVANCE: The aim of this research is to understand mechanisms through which nitric oxide derivatives resist development of cardiovascular disease especially those related to vascular inflammation. Results from our studies will provide insight into prevention and development of potential therapeutic strategies.