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 -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.