title: Microsomal prostaglandin synthase-1-derived prostaglandin E2 protects against angiotensin II-induced hypertension via inhibition of oxidative stress.
abstract: Prostaglandin (PG) E(2) has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1(+/+) mice but induced a marked hypertensive response in mPGES-1(-/-) mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47(phox), gp91(phox), and Nox1. The hypertension in mPGES-1(-/-) mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure-lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47(phox), gp91(phox), and Nox1 that were all inhibited by PGE(2). The -/- mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1-derived PGE(2) buffers Ang II-induced vasoconstriction via inhibition of NADPH oxidase-dependent reactive oxygen species production.
authors.affiliation: Department of Internal Medicine, University of Utah and Veterans' Affairs Medical Center, Salt Lake City, UT 84132, USA.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Guo
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006973:Hypertension / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000071876:Prostaglandin-E Synthases; D017382:Reactive Oxygen Species / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D008562:Membrane Glycoproteins; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D017382:Reactive Oxygen Species; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000804:Angiotensin II; D009569:Nitric Oxide; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C060505:neutrophil cytosolic factor 1; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C000605866:Ptges2 protein, mouse