In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 1 ( 2016-01), p. 108-121
Abstract:
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 PGE 2 production by COX-1– and COX-2–specific inhibitors in high–Pi-stimulated VSMCs, indicating the involvement of PGE 2 during COX-2 inhibition-aggravated vascular calcification. Indeed, exogenous PGE 2 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 PGE 2 receptors indicated EP4 may mediate PGE 2 -inhibited vascular calcification. Conclusions— Our data revealed the pivotal role of COX-2–mPGES-1–PGE 2 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.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/ATVBAHA.115.306642
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2016
detail.hit.zdb_id:
1494427-3
