Microsomal Prostaglandin E Synthase-1–Derived PGE2 Inhibits Vascular Smooth Muscle Cell Calcification

Objective—Chronic administration of selective cyclooxygenase-2 (COX-2) inhibitors leads to an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. Vascular smooth muscle cell (VSMC) calcification, a common complication of chronic kidney disease, is directly related to cardiovascular morbidity and mortality. Here, we tested whether specific COX-2 inhibition affects vascular calcification during chronic renal failure. Approach and Results—The COX-2–specific inhibitors NS398 and SC236 significantly increased high–phosphate (Pi)-induced VSMC calcification. Similarly, COX-2−/− VSMCs, COX-2−/− aortas rings treated with high Pi and adenine diet–induced COX-2−/− chronic renal failure mice displayed enhanced calcium deposition. Metabolomic analysis revealed the differential suppression of PGE2 production by COX-1– and COX-2–specific inhibitors in high–Pi-stimulated VSMCs, indicating the involvement of PGE2 during COX-2 inhibition-aggravated vascular calcification. Indeed, ex...