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 subsequent adverse cardiovascular events during chronic renal failure.
- Received September 26, 2015.
- Accepted October 15, 2015.
- © 2015 American Heart Association, Inc.