Lack of microsomal prostaglandin E 2 synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction

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Abstract

Background-Microsomal prostaglandin E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E 2 biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges -/- mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges ++ mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow-derived leukocytes in the recovery of LV function after coronary ligation. Methods and Results-Cardiac structure and function in Ptges ++ mice with Ptges ++ bone marrow (BM) and Ptges ++ mice with Ptges -/- BM (BM -/-) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography-tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM -/- mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM ++ mice. BM -/- mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM ++ mice. Levels of prostaglandin E 2 were higher in the infarct and viable myocardium of BM -/- mice than in BM ++ mice. Conclusions-Lack of mPGES-1 in bone marrow-derived leukocytes negatively regulates COX-1 expression, prostaglandin E 2 biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction. © 2012 American Heart Association, Inc.

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Degousee, N., Simpson, J., Fazel, S., Scholich, K., Angoulvant, D., Angioni, C., … Rubin, B. B. (2012). Lack of microsomal prostaglandin E 2 synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction. Circulation, 125(23), 2904–2913. https://doi.org/10.1161/CIRCULATIONAHA.112.099754

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