COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells.

Cardiovascular safety of cyclooxygenase (COX)-2-selective inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of worldwide concern. COX-2 inhibitors and NSAIDs act by inhibiting arachidonic acid metabolism to prostaglandins. They confer a cardiovascular hazard manifested as an elevated risk of myocardial infarction. Mechanisms underlying these cardiovascular effects are uncertain. Here we determine whether interference with cytosolic phospholipase A2 (cPLA-2) or COX-2 through pharmacologic blockade or silencing RNA impacts expression of scavenger receptor CD36 and scavenger receptor A, both involved in cholesterol uptake in monocytes and macrophages. THP-1 human monocytes and human peripheral blood mononuclear cells were exposed to celecoxib, a COX-2 selective inhibitor currently in clinical use, and to arachidonyl trifluoromethyl ketone (AACOCF3), an arachidonic acid analog that selectively inhibits cPLA-2. Celecoxib and AACOCF3 each upregulated expression of CD36, but not scavenger receptor A, as determined by quantitative PCR and immunoblotting. Silencing of cPLA-2 or COX-2 had comparable effects to pharmacologic treatments. Oil red O staining revealed a profound increase in foam cell transformation of THP-1 macrophages exposed to either celecoxib or AACOCF3 (both 25 µM), supporting a role for the COX pathway in maintaining macrophage cholesterol homeostasis. Demonstration of disrupted cholesterol balance by AACOCF3 and celecoxib provides further evidence of the possible mechanism by which COX inhibition may promote lipid overload leading to atheromatous lesion formation and increased cardiovascular events.

Enhanced CD36 scavenger receptor expression in THP-1 human monocytes in the presence of lupus plasma: linking autoimmunity and atherosclerosis.

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.