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

Abstract

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.

• Authors: Cheng Gao, Yi Fu, Yanhui Li, Xu Zhang, Lu Zhang, Fang Yu, Susanna S Xu, Qingbo Xu, Yi Zhu, Youfei Guan, Xian Wang, Wei Kong
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 36 Issue 1 Pg. 108-21 (Jan 2016) ISSN: 1524-4636 [Electronic] United States
• PMID: 26543101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Phosphates
• Ptger4 protein, rat
• Receptors, Prostaglandin E, EP4 Subtype
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Ptgs2 protein, rat
• Intramolecular Oxidoreductases
• PTGES protein, human
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Ptges protein, rat
• Calcitriol
• Adenine
• Dinoprostone

Topics

• Adenine
• Animals
• Aorta, Abdominal (enzymology, pathology)
• Aorta, Thoracic (enzymology, pathology)
• Aortic Diseases (chemically induced, enzymology, genetics, prevention & control)
• Calcitriol
• Cells, Cultured
• Cyclooxygenase 2 (deficiency, genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (toxicity)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Humans
• Intramolecular Oxidoreductases (deficiency, genetics, metabolism)
• Kidney Failure, Chronic (chemically induced, enzymology, genetics)
• Male
• Metabolomics (methods)
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, enzymology, pathology)
• Myocytes, Smooth Muscle (drug effects, enzymology, pathology)
• Nephrectomy
• Phosphates
• Prostaglandin-E Synthases
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Rats, Sprague-Dawley
• Receptors, Prostaglandin E, EP4 Subtype (metabolism)
• Signal Transduction
• Time Factors
• Vascular Calcification (chemically induced, enzymology, genetics, prevention & control)