title: COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells.
abstract: 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.
authors.affiliation: Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Kamran
authors.initials: K
authors.lastname: Anwar
authors.forename: Iryna
authors.initials: I
authors.lastname: Voloshyna
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Littlefield
authors.forename: Steven E
authors.initials: SE
authors.lastname: Carsons
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wirkowski
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Jaber
authors.forename: Andrew
authors.initials: A
authors.lastname: Sohn
authors.forename: Sajan
authors.initials: S
authors.lastname: Eapen
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
mesh_terms: D001095:Arachidonic Acids / Q000009:adverse effects*; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics; D000068579:Celecoxib; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005487:Foam Cells / Q000201:enzymology*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000201:enzymology; D011720:Pyrazoles / Q000009:adverse effects*; D051117:Scavenger Receptors, Class A / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: D001095:Arachidonic Acids; D018955:CD36 Antigens; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D051117:Scavenger Receptors, Class A; D013449:Sulfonamides; C081565:arachidonyltrifluoromethane; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D054510:Phospholipases A2, Cytosolic; D000068579:Celecoxib