Lipoprotein, especially low-density lipoprotein (LDL), is an important risk factor for cardiovascular disease. LDL contributes to the atherogenic process, in part, by causing endothelial vasodilatory dysfunction and activation. Therefore, understanding how LDL alters endothelial function is an important problem in cardiovascular disease. Endothelial vasodilatory function and activation are regulated by endothelium-derived nitric oxide (NO), and evidence suggests that endothelium-derived NO attenuates atherogenesis and vascular inflammation. Previous work supported by this grant have shown that LDL attenuates endothelial NO synthase (eNOS) activity via effects on heterotrimeric and small guanine nucleotide-binding proteins (G proteins). Furthermore, the HMG-CoA reductase inhibitors or statins improve endothelial vasodilatory function, in part, by inhibiting the isoprenylation of the small G protein, Rho. These findings, therefore, form the basis of our hypothesis that heterotrimeric and small G proteins play an important role in mediating LDL-induced endothelial cell dysfunction and activation. The precise mechanism by which LDL modulates G protein function, however, is not known. The overall goal of this grant proposal, therefore, is to investigate the mechanism by which lipoproteins and statins regulate endothelial G protein function and to correlate these effects with functional changes in receptor-mediated eNOS activity and lipoprotein-induced endothelial cell activation. In this competitive renewal application, we have proposed 4 specific aims, which will extend our previous studies on LDL's effect on G proteins and eNOS.
In specific aim 1, we will test the hypothesis that inhibition of G proteins by LDL is mediated by regulators of G-protein signaling (RGS).
In specific aim 2, we will determine whether statins can reverse LDL's inhibitory effect on G proteins by cholesterol-independent mechanism.
In specific aim 3, we will test the hypothesis that lipoproteins downregulate eNOS expression and activity by activating Rho-mediated pathways. Finally, in specific aim 4, we will test the functional significance of statin-induced eNOS activation by investigating the effects of statin on LDL-induced endothelial cell activation. These proposed studies will hopefully provide greater insights into how lipoproteins cause endothelial dysfunction.
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