Myeloid Cell mPges-1 Deletion Attenuates Mortality Without Affecting Remodeling After Acute Myocardial Infarction in Mice

Abstract

Selective deletion of microsomal prostaglandin E 2 synthase-1 (mPges-1) in myeloid cells retards atherogenesis and suppresses the vascular proliferative response to injury, while it does not predispose to thrombogenesis or hypertension. However, studies using bone marrow transplants from irradiated mice suggest that myeloid cell mPGES-1 facilitates cardiac remodeling and prolongs survival after experimental myocardial infarction (MI). Here, we addressed this question using mice lacking mPges-1 in myeloid cells, particularly macrophages [Mac-mPges-1-knockout (KO)], generated by crossing mPges-1 floxed mice with LysMCre mice and subjecting them to coronary artery ligation. Cardiac structure and function were assessed by morphometric analysis, echocardiography, and invasive hemodynamics 3, 7, and 28 days after MI. Despite a similar infarct size, in contrast to the prior report, the post-MI survival rate was markedly improved in the Mac-mPges-1-KO mice compared with wild-type controls. Left ventricular systolic (reflected by ejection fraction, fractional shortness end systolic volume, and 1dP/dt) and diastolic function (reflected by end diastolic volume, 2dP/dt, and Tau), cardiac hypertrophy (reflected by left ventricular dimensions), and staining for fibrosis did not differ between the groups. In conclusion, we found that Cre-loxP-mediated deletion of mPges-1 in myeloid cells has favorable effects on post-MI survival, with no detectable adverse influence on post-MI remodeling. These results add to evidence that targeting macrophage mPGES-1 may represent a safe and efficacious approach to the treatment and prevention of cardiovascular inflammatory disease.

Microsomal Prostaglandin E2 Synthase-1 Deletion Attenuates Isoproterenol-Induced Myocardial Fibrosis in Mice

“…However, the role of mPGES-1 in pathological cardiac remodeling and heart dysfunction is still in debate. Although studies had reported impaired post-ischemic heart function and cardiac remodeling in mPGES-1 deficient mice (Degousee et al, 2008;Zhu et al, 2019), we and others failed to observe any adverse influence on cardiac remodeling after mPGES-1 was deleted globally or selectively in myeloid cells (Chen et al, 2019;Wu et al, 2009b). Moreover, in a model of Ang II mediated cardiac remodeling, although lack of mPGES-1 did not affect cardiac hypertrophy and fibrosis, nevertheless poor cardiac function was observed (Harding, Yang, He, & This article has not been copyedited and formatted.…”

“…Moreover, Degousee et al showed that either global or myeloid cell mPGES-1 deletion adversely interfered with cardiac remodeling and cut down survival after experimental myocardial infarction in mice (Degousee et al, 2008;Degousee et al, 2012). However, in a sharp contrast, we recently demonstrated that inhibition of mPGES-1, especially in macrophages, might be beneficial to survival without worsen post-MI cardiac dysfunction (Chen et al, 2019). Although there are many possible explanations for the above discrepancies, the complexity of the role of mPGES-1 in myocardial remodeling requires further investigation.…”

Microsomal prostaglandin E synthase‐1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice

“…Other studies have found increased survival after MI with no evidence of adverse cardiac remodelling in mice with myeloid‐specific mPGES‐1 knockout, and global deletion of mPGES‐1 did not worsen post‐MI cardiac dysfunction (Chen et al, 2019). However, it was also reported that mPGES‐1, especially in myeloid cells, was required for LV function after MI (Degousee et al, 2008, 2012).…”

“…In a mouse model of MI, global deletion of mPGES‐1 or its deletion in bone marrow‐derived myeloid cells impaired cardiac remodelling after MI (Degousee et al, 2008, 2012). Recently, another study showed that global deletion of mPGES‐1 did not exacerbate cardiac dysfunction after MI, whereas myeloid‐specific deletion of mPGES‐1 had favourable effects on post‐MI survival, with no detectable adverse cardiac remodelling (Chen et al, 2019). Recently, we reported that deletion of mPGES‐1 exacerbated acute myocardial ischaemia/reperfusion (I/R) injury (Zhu et al, 2019).…”

Epithelial Cell-specific Deletion of Microsomal Prostaglandin E Synthase-1 Does Not Influence Colon Tumor Development in Mice

“…In fact, Chen et al [18][19][20] generated a Ptges-Cre-Loxp mouse model to specifically delete the Ptges gene in vascular smooth muscle cells, endothelial cells and myeloid cells in order to study its potential role in cardiovascular diseases. While vascular smooth muscle-specific deletion of Ptges did not impact atherogenesis [19], deletion in myeloid cells attenuated the vascular proliferative response to injury during high-fat diet-induced atherogenesis [19], and also showed beneficial effects during the healing of myocardial infarction [20]. These observations provide further evidence of the multifaceted role of mPGES-1 in a variety of experimental systems in cell type-specific manner, as comprehensively reviewed earlier [1].…”