Microsomal Prostaglandin E 2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction

Abstract

Background— Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE 2 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 α- 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 PGE 2 but not PGD 2 , thromboxane A 2 , PGI 2 , or PGF 2α 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 PGE 2 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.