Lack of Microsomal Prostaglandin E2 Synthase-1 in Bone Marrow Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality after Acute Myocardial Infarction
Background—Microsomal prostaglandin E2 synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes PGE2 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 (LVEDP) than Ptges+/+ mice after MI. 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−/−) was assessed by morphometric analysis, echocardiography and invasive hemodynamics before, 7 and 28 days after MI. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by LC-MS/MS and real time PCR, immunoblotting, immunohistochemistry and immunofluorescence microscopy, respectively. After MI, BM−/− mice have more LV dilation, worse LV systolic and diastolic function, higher LVEDP, more cardiomyocyte hypertrophy and higher mortality, but similar infarct size and pulmonary edema than BM+/+ mice. BM−/− mice also have higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM+/+ mice. Levels of PGE2 are higher in the infarct and viable myocardium of BM−/− than BM+/+ mice.
Conclusions—Lack of mPGES-1 in bone marrow derived leukocytes negatively regulates COX-1 expression, PGE2 biosynthesis and inflammation in the infarct, and leads to impaired LV function, adverse LV remodeling and decreased survival after acute MI.
- Received February 17, 2012.
- Accepted April 4, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited