Microsomal prostaglandin E synthase-1 deletion suppresses oxidative stress and angiotensin II-induced abdominal aortic aneurysm formation.

Abstract

BACKGROUND:

Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH(2) into PGE(2). Deletion of mPGES-1 modulates experimentally evoked pain and inflammation and retards atherogenesis. The role of mPGES-1 in abdominal aortic aneurysm is unknown.

METHODS AND RESULTS:

The impact of mPGES-1 deletion on formation of angiotensin II-induced abdominal aortic aneurysm was studied in mice lacking low-density lipoprotein receptor (LDLR(-/-)). Male mice deficient in both mPGES-1 and LDLR (mPGES-1(-/-) LDLR(-/-)) and littermate LDLR(-/-) mice were initiated on a high-fat diet at 6 months of age, followed 1 week later by continuous infusion of angiotensin II (1 microg/kg per minute) for an additional 4 weeks. Angiotensin II infusion upregulated aortic expression of cyclooxygenase-2 and mPGES-1, increased aortic macrophage recruitment and vascular nitrotyrosine staining (which reflects local oxidative stress), and augmented urinary excretion of the isoprostane 8,12-iso-iPF(2alpha)-VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE(2) (PGE-M). Deletion of mPGES-1 decreased both the incidence (87.5% versus 27.3%; P=0.02) and the severity of abdominal aortic aneurysm and depressed the aortic and systemic indices of oxidative stress. Deletion of mPGES-1 also depressed urinary PGE-M, whereas it augmented excretion of PGD(2) and PGI(2) metabolites, reflecting rediversion of the accumulated PGH(2) substrate in the double knockouts.

CONCLUSIONS:

Deletion of mPGES-1 protects against abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice, coincident with a reduction in oxidative stress. The potential efficacy of selective inhibition of mPGES-1 in preventing or retarding aneurysm formation warrants further investigation.

• Authors: Miao Wang, Eric Lee, Wenliang Song, Emanuela Ricciotti, Daniel J Rader, John A Lawson, Ellen Puré, Garret A FitzGerald
• Journal: Circulation (Circulation) Vol. 117 Issue 10 Pg. 1302-9 (Mar 11 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18285567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Prostaglandins
• Receptors, LDL
• Angiotensin II
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases
• Ptges protein, mouse

Topics

• Angiotensin II (pharmacology)
• Animals
• Aortic Aneurysm, Abdominal (chemically induced, prevention & control)
• Hyperlipidemias (complications)
• Intramolecular Oxidoreductases (deficiency, genetics, physiology)
• Male
• Mice
• Mice, Knockout
• Oxidative Stress (drug effects)
• Prostaglandin-E Synthases
• Prostaglandins (metabolism)
• Receptors, LDL (deficiency, genetics)
• Up-Regulation