Cholesterol in Rheumatoid Arthritis and Lupus
“Atherosclerosis in Rheumatoid Arthritis and Lupus: Restoring Cholesterol Balance”
Hypothesis: SLE and RA increase risk of myocardial infarction (MI, heart attack). Immune reactants in the circulation of SLE patients downregulate cholesterol efflux proteins 27-hydroxylase and ABCA1 and upregulate scavenger receptor CD36, thus encouraging cholesterol accumulation. Adenosine A2A receptor agonist or statin treatment of cells exposed to SLE plasma (or immune complexes or cytokine-enriched plasma fractions from SLE patients) may ameliorate inflammatory properties of their plasma, lessening its atherogenic potency. Rationale: SLE and RA plasma contain components not present in significant levels in normal plasma that could, individually or acting together, affect 27-hydroxylase, ABCA1 and CD36 expression. Candidate components include autoantibodies, immune complexes, and various cytokines. Statins reduce major cardiovascular events and death. Modulation of adenosine signaling participates in regulation of 27-hydroxylase and ABCA1. As a potential preventative and therapeutic approach to atherosclerotic cardiovascular disease, the investigators evaluate the effect of A2A receptor agonists and statins on atherogenic parameters in SLE and RA plasma. Experimental Plan: Quantitate 27-hydroxylase and several other proteins involved in cellular cholesterol uptake and excretion in THP-1 monocytes/macrophages and HAEC after exposure to plasma and plasma components from SLE patients (and controls) A? lipid loading with acetylated LDL with/without addition of A2AR agonist, statin, or both. Determine relative impact of immune complexes and cytokines on expression of proteins involved in cholesterol flux. Determine levels of proteins involved in cellular cholesterol influx/efflux in peripheral blood mononuclear cells isolated from RA, SLE and psoriatic arthritis patients and normal controls at baseline, then following incubation in culture media alone or with statin, adenosine A2A agonist or both statin + A2AR agonist.
Atherosclerosis in RA and Lupus: Restoring Cholesterol Balance