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

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 Ϫ/Ϫ mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges ϩ/ϩ 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 Ptgesϩ/ϩ mice with Ptges ϩ/ϩ bone marrow (BM ϩ/ϩ ) and Ptges ϩ/ϩ mice with Ptges Ϫ/Ϫ BM (BM Ϫ/Ϫ ) 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 Ϫ/Ϫ 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 ϩ/ϩ mice. BM Ϫ/Ϫ mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM ϩ/ϩ mice. Levels of prostaglandin E 2 were higher in the infarct and viable myocardium of BM Ϫ/Ϫ mice than in BM ϩ/ϩ 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. (Circulation. 2012;125:2904-2913.)Key Words: leukocytes Ⅲ myocardial infarction Ⅲ prostaglandins Ⅲ remodeling Ⅲ chimeric mice I schemic heart disease and myocardial infarction (MI) will be the leading cause of death worldwide by 2020. 1 MI leads to an inflammatory response characterized by the generation of proinflammatory mediators and the influx of leukocytes that are necessary to remove necrotic cellular debris and promote recovery of left ventricular (LV) contractile function. An improperly regulated inflammatory response and pathological LV remodeling can impair LV function and lead to heart failure and death after MI. 2,3 Editorial see p 2818 Clinical Perspective on p 2913Prostaglandins, synthesized by the sequential action of phospholipase A 2 (PLA 2 ), cyclooxygenases (COX-1 and/or Received November 28, 2011; accepted April 4, 2012. 12 Collectively, these observations suggest a beneficial role for mPGES-1-mediated PGE 2 biosynthesis in postinfarction LV remodeling. The cellular source of mPGES-1 in the heart after MI has not been identified. In this study, we show that deletion of mPGES-1 in bone marrow-derived leukocytes results in a more intense inflammatory response, patholog...

Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion

“…Because platelet ERK5 is activated by ROS, thrombin, and thromboxane, ERK5 activation in an ischemic environment was explored using a mouse myocardial infarction (MI) model in which these mediators have significant pathologic roles 28–30 . As a chronic MI model the left anterior descending (LAD) coronary artery was permanently ligated.…”

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE2 Receptors in Cardiovascular Health and Diseases

“…It was found that the induction of the mPGES-1 protein was mainly produced from inflammatory cells of the heart after myocardial infarction [15]. Thus, by using the bone marrow transplant approach, Degousee's group further demonstrated that inactivation of mPGES-1 in bone marrow-derived leukocytes fully replicated the deleterious remodeling phenotypes and decreased the post-MI survival [70]. Surprisingly, although mPGES-1 was lacking in bone marrow leukocytes, an even higher level of PGE 2 was detected in infarct and viable myocardium.…”

Activation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction

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