Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Numerous investigations by our group and others have indicated cardioprotective and anti-inflammatory properties of resveratrol. The present study explored potential atheroprotective actions of resveratrol on cholesterol efflux in cultured human macrophages exposed to plasma from systemic lupus erythematosus (SLE) patients. These results were confirmed in ApoEknockout mice, displaying a lupus profile with accelerated atherosclerosis. Resveratrol treatment attenuated atherosclerosis in these mice. THP-1 human macrophages were exposed to 10% pooled or individual plasma from patients who met diagnostic criteria for SLE. Expression of multiple proteins involved in reverse cholesterol transport (ABCA1, ABCG1, SR-B1, and cytochrome P450 27-hydroxylase) was assessed using QRT-PCR and Western blotting techniques. Ten-week-old ApoE(n ¼ 30) were randomly divided into two equal groups of 15, one of which received 0.01% resveratrol for 10 consecutive weeks. Atherosclerosis progression was evaluated in murine aortas. Bone marrow-derived macrophages (BMDM) were cultured and expression of cholesterol efflux proteins was analyzed in each group of mice. Our data indicate that inhibition of cholesterol efflux by lupus plasma in THP-1 human macrophages is rescued by resveratrol. Similarly, administration of resveratrol in a lupus-like murine model reduces plaque formation in vivo and augments cholesterol efflux in BMDM. This study presents evidence for a beneficial role of resveratrol in atherosclerosis in the specific setting of SLE. Therefore, resveratrol may merit investigation as an additional resource available to reduce lipid deposition and atherosclerosis in humans, especially in such vulnerable populations as lupus patients.
The Cardiovascular Inflammation Reduction Trial (CIRT) was designed to assess whether low-dose methotrexate (LD-MTX) would reduce future cardiac events in patients with metabolic syndrome or type 2 diabetes (T2DM) who are post-myocardial infarction (MI) or have multivessel disease. Our previous work indicates that MTX confers atheroprotection via adenosine A2A receptor (A2AR) activation. In order for A2AR ligation to reduce cardiovascular events, A2AR levels would need to be preserved during MTX treatment. This study was conducted to determine whether LD-MTX alters peripheral blood mononuclear cell (PBMC) adenosine receptor expression in persons at risk for cardiovascular events. Post-MI T2DM CIRT patients were randomized to LD-MTX or placebo (n=10/group). PBMC isolated from blood drawn at enrollment and after 6 weeks were evaluated for expression of adenosine receptors and reverse cholesterol transporters by real-time PCR. Fold change between time points was calculated using factorial analyses of variance. Compared with placebo, the LD-MTX group exhibited a trend toward an increase in A2AR (p=0.06), while A3R expression was significantly decreased (p=0.01) after 6 weeks. Cholesterol efflux gene expression did not change significantly. Persistence of A2AR combined with A3R downregulation indicates that failure of MTX to be atheroprotective in CIRT was not due to loss of adenosine receptors on PBMC (ClinicalTrials.gov identifier: NCT01594333).
Purpose of StudyPremature atherosclerosis with coronary artery disease is a major cause of morbidity in Systemic Lupus Erythematosus (SLE). SLE patient plasma induces a pro-atherogenic profile of cholesterol transport genes in macrophages. A common immunosuppressive treatment for SLE, mycophenolate (MMF) reduces scavenger receptors thus reducing lipid influx. We have demonstrated atheroprotective properties of the polyphenol resveratrol on cholesterol efflux. This study determines whether MMF and resveratrol work synergistically to regulate cholesterol transport in macrophages exposed to pro-atherogenic SLE plasma.Methods UsedTHP-1 human macrophages (106/ml) were incubated in 10% SLE plasma with: media (control); MMF (1 µg/ml); resveratrol (50 µM); and MMF+resveratrol. After 24 h incubation, total RNA and protein were isolated. Message level of scavenger receptors CD36, LOX1, and SRA1; and efflux proteins 27-hydroxylase, ATP binding cassette transporter (ABC)A1, and ABCG1 were evaluated by QRT-PCR and confirmed by immunoblot. Cholesterol efflux was measured by Amplex Red Cholesterol Assay kit run±cholesterol esterase.Summary of ResultsIn 10% SLE plasma, MMF suppressed efflux genes ABCA1 and ABCG1 (58.38±3.5% and 72.98±3.3%) vs. SLE plasma alone (p<0.0001) while MMF+resveratrol corrected this suppression. In SLE plasma, MMF+resveratrol decreased ScrA1 and LOX-1 by 15±2.5% and 47±1.0%, respectively vs. resveratrol alone (p<0.0001). SLE plasma promoted cholesterol accumulation in THP-1 macrophages and prevented efflux into medium. It increased the ratio of cholesterol esters to free cholesterol (ChE/FC). Resveratrol decreased intracellular cholesterol and restored ChE/FC ratios to that of cells in healthy control plasma.ConclusionsMMF and resveratrol exhibit complimentary effects on macrophages exposed to SLE plasma. Both agents combined restore cholesterol influx and efflux gene expression to that of cells treated with control plasma. Resveratrol additionally reverses cholesterol accumulation caused by SLE plasma. Further evaluation of resveratrol+MMF in atherosclerosis in SLE may lead to improved treatment.
Objective: Atherosclerosis contributes to 30% of deaths in systemic lupus erythematosus (SLE) and cardiovascular mortality is 50% higher in rheumatoid arthritis (RA) than in the general population. Little is known about mechanisms leading to progression of atherosclerosis at the cellular level. Here we analyze expression of key cholesterol transport proteins that impact atheroma development in BMDM from KRNAg7 (RA) and apoE‐/‐Fas‐/‐ (SLE) mice as disease evolves. Methods: Male homozygous C57BL/6J, apoE‐/‐ , apoE‐/‐Fas‐/‐ , KRN and KRNAg7 mice (n=5 per group) were studied. Femurs were dissected and cell suspensions obtained by flushing bones. BMDM were generated by culturing cells for 7 days with MCSF. Expression of efflux proteins ATP binding cassette transporters (ABC)A1 and ABCG1, and scavenger receptors CD36 and LOX1 were evaluated by QRT‐PCR. Results: 6 wk mice had no significant changes in cholesterol efflux proteins. 30 wk apoE‐/‐, apoE‐/‐Fas‐/‐ mice display 2‐fold reduction in ABCA1 and ABCG1 mRNA (n=3, P<0.01). 6 wk KRNAg7 mice show increased CD36 (225.5±54% vs. wt mice at 100%) (n=3, P<0.01). LOX‐1 did not differ significantly from C57BL/6J and KRN mice. ApoE‐/‐Fas‐/‐ mice had increase in CD36 mRNA (150±23% at 6 wk; 161.3±12.3% at 30 wk, n=3, P<0.05) LOX1 expression was unchanged. In contrast, apoE‐/‐ mice display a 2‐fold increase in both CD36 and LOX1 at 6 wk and up to a 5‐fold increase at 30 wk. Conclusions: This study provides insight into molecular alterations that contribute to atherogenesis in SLE and RA. We demonstrate that imbalance between cholesterol efflux and influx contributes to atherosclerosis progression. Further metabolic screening may identify optimal time‐points for intervention.
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