title: Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion.
abstract: Our laboratory previously reported that inducible PGE(2) synthase, mPGES-1, contributes to micromolar production of PGE(2) in neonatal ventricular myocytes in vitro, which stimulates their growth. We therefore hypothesized that mPGES-1 contributes to cardiac hypertrophy following angiotensin II (ANG II) infusion. To test this hypothesis, we used 10- to 12-wk-old mPGES-1 knockout mice (mPGES-1 KO) and C57Bl/6 control mice infused for 8 wk with either 1.4 mg · kg(-1) · day(-1) ANG II or vehicle subcutaneously. Blood pressure [systolic blood pressure (SBP)] was measured throughout the study, and cardiac function was assessed by M-mode echocardiography at baseline and at 8 wk of infusion. At the conclusion of the study, immunohistochemistry was used to evaluate collagen fraction, myocyte cross-sectional area (MCSA), and apoptosis. At baseline, there was no difference in SBP between mPGES-1 KO mice and C57BL/6 controls. ANG II infusion increased SBP to similar levels in both strains. In control mice, infusion of ANG II increased MCSA and posterior wall thickness at diastole (PWTd) but had little effect on cardiac function, consistent with compensatory hypertrophy. In contrast, cardiac function was worse in mPGES-1 KO mice after ANG II treatment. Ejection fraction declined from 76.2 ± 2.7 to 63.3 ± 3.4% after ANG II, and left ventricular dimension at systole and diastole increased from 1.29 ± 0.02 to 1.78 ± 0.15 mm and from 2.57 ± 0.03 to 2.90 ± 0.13 mm, respectively. Infusion of ANG II increased both the LV-to-body weight and the mass-to-body weight ratios to a similar extent in both strains. However, PWTd increased by a lesser extent in KO mice, suggesting an impaired hypertrophic response. ANG II infusion increased collagen staining similarly in both strains, but TdT-dUTP nick end labeling staining was greater in mPGES-1 KO mice. Overall, these results are consistent with a beneficial effect for mPGES-1 in the maintenance of cardiac function in ANG II-dependent hypertension.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. phardin1@hfhs.org
authors.forename: Pamela
authors.initials: P
authors.lastname: Harding
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Quan
authors.initials: Q
authors.lastname: He
authors.forename: Margot C
authors.initials: MC
authors.lastname: Lapointe
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D004452:Echocardiography; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D000804:Angiotensin II; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse