Premature cardiovascular disease is a major cause of mortality in patients with systemic lupus erythematosus (SLE) with the risk of myocardial infarction increased up to 50-fold. In the initial funding period we have shown that the prevalence of coronary artery atherosclerosis is increased remarkably in SLE, but the mechanisms remain unclear. Based on our preliminary data we propose that two related mechanisms - pro-atherogenic inflammatory mediators and the metabolic syndrome - predispose to accelerated atherosclerosis in SLE. In addition to defining the mechanisms for accelerated atherosclerosis it is important to define the effects of drugs used to reduce cardiovascular risk in high-risk patients. Low dose aspirin, by inhibiting thromboxane A2 biosynthesis, has profound antiplatelet effects, but some patients have impaired thromboxane suppression - a phenomenon termed aspirin resistance. An explanation is that aspirin-independent thromboxane synthesis may occur through enhanced COX-2 activity, as would occur in an inflammatory condition such as lupus. However, little is known about the effects of low-dose aspirin in SLE.rThus, we propose to test the following hypotheses: 1) that accelerated coronary artery atherosclerosis in SLE is associated with the metabolic syndrome and increased concentrations of inflammatory mediators; 2) that aspirin insensitive thromboxane biosynthesis is increased in patients with lupus and is mediated by increased COX-2 activity. Continuation of the proposed studies will build on our initial findings and generate important information regarding the inter-relationship between inflammation and atherosclerosis, and suggest strategies for reversing or preventing accelerated atherosclerosis in SLE, and potentially other diseases. Lay Summary: The risk of heart attack is almost 50 times in higher in patients with lupus than healthy people. Our study will find out what causes accelerated atherosclerosis in lupus and why some patients do not respond to aspirin. ? ?
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