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(Circulation. 2008;117:1701-1710.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Microsomal Prostaglandin E₂ Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction

Norbert Degousee, PhD^*; Shafie Fazel, MD, PhD^*; Denis Angoulvant, MD, PhD^*; Eva Stefanski, MSc; Sven-Christian Pawelzik, BSc; Marina Korotkova, PhD; Sara Arab, PhD; Peter Liu, MD, PhD; Thomas F. Lindsay, MD, MSc; Sun Zhuo, PhD; Jagdish Butany, MD; Ren-Ke Li, PhD; Laurent Audoly, PhD; Ronald Schmidt, PhD; Carlo Angioni; Gerd Geisslinger, MD, PhD; Per-Johan Jakobsson, MD, PhD; Barry B. Rubin, MD, PhD

From the Divisions of Vascular Surgery (N.D., E.S., T.F.L., B.B.R.), Cardiac Surgery (S.F., D.A., S.Z., R.-K.L.), Cardiology (S.A., P.L.), and Pathology (J.B.) and the Toronto General Hospital Research Institute of the University Health Network and the Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Rheumatology Unit and Karolinska Biomic Center, Karolinska University Hospital, Stockholm, Sweden (S.-C.P., M.K., P.-J.J.); Pfizer, Arthritis and Inflammation Research, Chesterfield, Mo (L.A.); Institut für Klinische Pharmakologie, Frankfurt am Main, Germany (R.S., C.A., G.G.). Dr Angoulvant currently is at Inserm U886, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Correspondence to Barry B. Rubin, Division of Vascular Surgery, 200 Elizabeth St, EN6–222, Toronto General Hospital, Toronto, Ontario, Canada M5G-2C4. E-mail barry.rubin{at}uhn.on.ca

Received September 1, 2007; accepted January 16, 2008.

Background— Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E₂ synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE₂ biosynthetic pathway. We caused acute MI in Ptges^+/+ and Ptges^–/– mice to define the role of mPGES-1 in cardiac ischemic injury.

Methods and Results— Twenty-eight days after MI, Ptges^–/– mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges^+/+ mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges^–/– than Ptges^+/+ mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges^–/– mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and - and β-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges^–/– than Ptges^+/+ mice after MI. Ptges^+/+ mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges^–/– mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE₂ but not PGD₂, thromboxane A₂, PGI₂, or PGF₂ are higher in the infarct and LV remote from the infarct after MI in Ptges^+/+ than Ptges^–/– mice.

Conclusions— In Ptges^+/+ mice, mPGES-1 in inflammatory cells catalyzes PGE₂ biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.

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