Despite advances in treatment, premature development of atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality in persons living with systemic lupus erythematosus (lupus, SLE). The ability of the physician to treat these vulnerable patients effectively is limited, particularly du to the inadequacy of their response to classic medications such as statins. There is a clear need to develop novel therapeutic modalities so that these susceptible patients, who are often young women, can be targeted for aggressive preventative interventions. Our laboratory has uncovered a strong association between inflammatory mediators (found at elevated levels in SLE) and disruption of normal cholesterol trafficking. These mediators interfere with atheroprotective cholesterol transport processes by dysregulating expression of genes that control cellular lipid homeostasis. We further demonstrated that the phytochemical resveratrol (3,4',5- trihydroxytrans-stilbene) improves cholesterol handling in human macrophages and endothelium by enhancing cholesterol efflux and limiting cholesterol uptake in vitro. Resveratrol is a natural anti-inflammatory compound present in grapes and red wine that we have found attenuates expression of specific scavenger receptors, upregulates expression of crucial cholesterol efflux proteins and prevents cytokine-mediated injurious changes in the level of these proteins. Overall, resveratrol acts to prevent lipid overload and decrease foam cell transformation, a hallmark event in atherogenesis. In cultured human macrophages we have shown that resveratrol can prevent suppression of cholesterol efflux proteins by SLE plasma. We hypothesize that resveratrol can correct adverse effects of inflammatory processes on cellular cholesterol homeostasis and may provide a novel target for therapeutic intervention to prevent ASCVD in the lupus population. Ultimately, as we move toward personalized medical regimens, those most likely to benefit from resveratrol may be given this dietary supplement based on pharmacogenetic tests of lipid-regulating genes. To characterize the pathways involved in the anti-atherogenic properties of resveratrol in the autoimmune setting we propose 2 aims: 1) Define the specific signaling systems responsible for the enhancement of cholesterol mobilization by resveratrol. Based on our preliminary studies, we look specifically at pathways shared by resveratrol and the purine nucleoside adenosine, a potent intermediate of myocardial preservation released in humans upon exposure to resveratrol. 2) Evaluate the impact of therapeutic intervention with resveratrol (under conditions of both high fat diet and normal chow diet) on atherosclerosis development, cholesterol transport gene expression profile and cholesterol flux in the ApoE-/- Fas-/- (lpr/lpr) mouse, a lupus susceptible murine model of atherosclerosis. To validate our hypothesis that resveratrol impedes development of atherosclerosis via effects on cholesterol flux in the vessel wall, we will examine the vasculature in vivo in this animal model prior to consideration of human testing.
We have found that the persistent inflammatory state in persons with systemic lupus erythematosus (SLE) accelerates atherosclerosis by disrupting cholesterol dynamics, increasing vulnerability to lipid overload in cells of the artery wall, including macrophages and endothelium. Resveratrol, a natural phytochemical, exhibits multiple anti-inflammatory and anti-atherogenic properties, most prominently by facilitating cholesterol removal through regulation of proteins critical for cholesterol efflux. This proposal fills an urget need to improve cardiovascular outcomes in SLE by combining cell culture studies with a murine model of atherosclerosis in an autoimmune setting in order to explore the potential novel cardioprotective therapeutic use of resveratrol to improve cholesterol balance.
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