Faculty Bibliography

Atherosclerotic cardiovascular disease (ASCVD) contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Immunologic derangements may disrupt cholesterol balance in vessel wall monocytes/macrophages and endothelium. We determined whether lupus plasma impacts expression of cholesterol 27-hydroxylase, an anti-atherogenic cholesterol-degrading enzyme that promotes cellular cholesterol efflux, in THP-1 human monocytes and primary human aortic endothelial cells (HAEC). THP-1 monocytes and HAEC were incubated in medium containing SLE patient plasma or apparently healthy control human plasma (CHP). SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47 +/- 8% (p < 0.008) and in HAEC by 51 +/- 5.5% (n = 5, p < 0.001). THP-1 macrophages were incubated in 25% lupus plasma or CHP and cholesterol-loaded (50 microg ml(-1) acetylated low density lipoprotein). Lupus plasma more than doubled macrophage foam cell transformation (74 +/- 3% vs. 35 +/- 3% for CHP, n = 3, p < 0.001). Impaired cholesterol homeostasis in SLE provides further evidence of immune involvement in atherogenesis. Strategies to inhibit or reverse arterial cholesterol accumulation may benefit SLE patients

Premature atherosclerotic cardiovascular disease (ASCVD) is a common and devastating complication of systemic lupus erythematosus (SLE). It is likely that immunologic derangements contribute to premature ASCVD in these patients, possibly by disrupting homeostatic mechanisms that orchestrate cholesterol balance in monocytes/macrophages in the artery wall. CD36, a macrophage scavenger receptor responsible for recognition and internalization of oxidized lipids, is a major participant in atherosclerotic foam cell formation. We hypothesized that lupus plasma would affect CD36 expression in a pro-atherogenic manner in THP-1 human monocytes and differentiated macrophages. SLE patient plasma markedly stimulated expression of CD36 message in a dose-dependent fashion in THP-1 human monocytes. A 50% volume/volume concentration of plasma derived from SLE patients increased CD36 mRNA by 71 +/- 8% (n = 3, P < 0.001) above 50% normal human plasma. 50% SLE patient plasma increased CD36 mRNA expression to 290 +/- 12% of no-plasma control (n = 3, P < 0.001), compared with only 118 +/- 3.7% of control in the presence of 50% normal human plasma (n = 3, not significant). 50% lupus plasma also upregulated CD36 protein expression by 482.3 +/- 76.2% (n = 4, P < 0.05), whereas the presence of 50% normal human plasma increased the CD36 protein level by only 239.8 +/- 61.9% (n = 4, P < 0.05). To our knowledge, this is the first demonstration that CD36 expression is enhanced by plasma from patients with an autoimmune disorder. Premature atherosclerosis is common in SLE patients. Upregulation of CD36 may contribute to this pathological process by increasing vulnerability to cholesterol overload. Demonstration of disrupted cholesterol homeostasis in this select group of patients provides further evidence of the involvement of the immune system in atherogenesis and may inform us of the role of CD36 in the general atherogenic process. CD36 may provide a novel therapeutic target in the treatment of ASCVD in SLE patients

OBJECTIVE: To determine whether methotrexate (MTX) can overcome the atherogenic effects of cyclooxygenase 2 (COX-2) inhibitors and interferon-gamma (IFNgamma), both of which suppress cholesterol efflux protein and promote foam cell transformation in human THP-1 monocyte/macrophages. METHODS: Message and protein levels of the reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) in THP-1 cells were evaluated by real-time polymerase chain reaction and immunoblot, respectively. Expression was evaluated in cells incubated in the presence or absence of the COX-2 inhibitor NS398 or IFNgamma, with and without MTX. Foam cell transformation of lipid-laden THP-1 macrophages was detected with oil red O staining and light microscopy. RESULTS: MTX increased 27-hydroxylase message and completely blocked NS398-induced down-regulation of 27-hydroxylase (mean +/- SEM 112.8 +/- 13.1% for NS398 plus MTX versus 71.1 +/- 4.3% for NS398 alone; P < 0.01). MTX also negated COX-2 inhibitor-mediated down-regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27-hydroxylase and ABCA1 was blocked by the adenosine A2A receptor-specific antagonist ZM241385. MTX also prevented NS398 and IFNgamma from increasing transformation of lipid-laden THP-1 macrophages into foam cells. CONCLUSION: This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in THP-1 macrophages. This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition. Our results suggest that one mechanism by which MTX protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall

Published studies and trials of oral and biologic disease-modifying antirheumatic drugs for the treatment of Sjögren's syndrome have shown disappointing results. Improvements in trial design, including development of consortia for the conduct of national and international multicenter studies and use of standardized classification and outcome measures coupled with the emergence of newer biologic, immunomodulatory, and small molecule agents, hopefully will result in the addition of disease-modifying agents to the armamentarium.

We present the first reported case of a patient with dermatomyositis found to have primary gastric melanoma. The possibility of primary gastric melanoma occurring before, concurrently or after the onset of dermatomyositis is the subject of this case report.

Both selective cyclooxygenase (COX)-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) have been beneficial pharmacological agents for many patients suffering from arthritis pain and inflammation. However, selective COX-2 inhibitors and traditional NSAIDs are both associated with heightened risk of myocardial infarction. Possible pro-atherogenic mechanisms of these inhibitors have been suggested, including an imbalance in prostanoid production leaving the pro-aggregatory prostaglandins unopposed, but the precise mechanisms involved have not been elucidated. We explored the possibility that downregulation of proteins involved in reverse cholesterol transport away from atheromatous plaques contributes to increased atherogenesis associated with COX inhibition. The reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) export cholesterol from macrophages. When mechanisms to process lipid load are inadequate, uncontrolled cholesterol deposition in macrophages transforms them into foam cells, a key element of atheromatous plaques. We showed that in cultured THP-1 human monocytes/macrophages, inhibition of COX-1, COX-2, or both reduced expression of 27-hydroxylase and ABCA1 message (real-time reverse transcription-polymerase chain reaction) and protein (immunoblot). The selective COX-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398) significantly reduced 27-hydroxylase and ABCA1 message (to 62.4% +/- 2.2% and 71.1% +/- 3.9% of control, respectively). Incubation with prostaglandin (PG) E2 or PGD2 reversed reductions in both of these cholesterol transport proteins induced by NS398. Cholesterol-loaded THP-1 macrophages showed significantly increased foam cell transformation in the presence of NS398 versus control (42.7% +/- 6.6% versus 20.1% +/- 3.4%, p = 0.04) as determined by oil red O staining. Pharmacological inhibition of COX in monocytes is involved in downregulation of two proteins that mediate cholesterol efflux: cholesterol 27-hydroxylase and ABCA1. Because these proteins are anti-atherogenic, their downregulation may contribute to increased incidence of cardiac events in patients treated with COX inhibitors. Reversal of inhibitory effects on 27-hydroxylase and ABCA1 expression by PGD2 and PGE2 suggests involvement of their respective signaling pathways. NS398-treated THP-1 macrophages show greater vulnerability to form foam cells. Increased cardiovascular risk with COX inhibition may be ascribed at least in part to altered cholesterol metabolism