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, exogenous PGE² reduced alkaline phosphatase activity, osteogenic transdifferentiation, apoptosis, and calcification of VSMCs. In accordance, downregulation of microsomal prostaglandin E synthase (mPGES)-1 in VSMCs, mPGES-1^-/- aorta with high-Pi stimulation and mPGES-1^-/- chronic renal failure mice resulted in enhanced vascular mineralization. Further applications of RNAi and specific antagonists for PGE² receptors indicated EP4 may mediate PGE²-inhibited vascular calcification. Conclusions-Our data revealed the pivotal role of COX-2-mPGES-1-PGE² axis in vascular calcification. The selective inhibition of COX-2 or mPGES-1 may increase the risk of calcification and supsequent adverse cardiovascular events during chronic renal failure.