Reduced Cardiac Remodeling and Function in Cardiac-Specific EP ₄ Receptor Knockout Mice With Myocardial Infarction

Abstract

Abstract-We have shown previously that cyclooxygenase-2 inhibition reduces cardiac hypertrophy and fibrosis postmyocardial infarction (MI) in a mouse model and that prostaglandin E 2 stimulates cardiomyocyte hypertrophy in vitro through its EP 4 receptor. Because the role of cardiac myocyte EP 4 in cardiac function and hypertrophy in vivo is unknown, we generated mice lacking EP 4 only in cardiomyocytes (CM-EP 4 knockout [KO]). Twelve-to 14-week-old mice were evaluated using echocardiography and histology. There were no differences in ejection fraction, myocyte cross-sectional area, and interstitial collagen fraction between KO mice and littermate controls. To test the hypothesis that EP 4 is involved in cardiac remodeling after MI, we induced MI by ligating the left anterior descending coronary artery. Two weeks later, the mice were subjected to echocardiography, and hearts were removed for histology and Western blot. There was no difference in infarct size between KO mice and controls; however, KO mice showed less myocyte cross-sectional area and interstitial collagen fraction than controls. Also, CM-EP4 KO mice had reduced ejection fraction. Because the transcription factor Stat-3 is involved in hypertrophy and protection from ischemic injury, we tested whether it was activated in control and KO mouse hearts after MI. Western blot indicated that Stat-3 was activated in control hearts after MI but not in KO hearts. Thus, CM-EP4 deletion decreased hypertrophy, fibrosis, and activation of Stat-3. However, cardiac function was unexpectedly worsened in these mice. We conclude that cardiac myocyte EP 4 plays a role in hypertrophy via activation of Stat-3, a process that seems to be cardioprotective.

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

“…PKA activity has been shown to have no relation with the development of cardiac hypertrophy in an in vivo rat pressure overload model, 32) however, PGE2 stimulation induced cardiomyocyte hypertrophy via EP4-cAMP-PKA axis, and via p44/42 and p38 MAPK in neonatal rat cardiomyocytes. [33][34][35][36][37] Cardiomyocyte-specific deletion of EP4 receptors showed less hypertrophy in a myocardial infarction model, 38) suggesting the possibility that PGE2-EP4 was involved in prohypertrophic responses. In this study, the administration of ONO-0260164 did not induce further progression of cardiac hypertrophy assessed by LV wall thickness and cross sectional area of the cardiac myocytes in vivo, indicating different hypertrophic responses to ONO-0260164 as compared to PGE2.…”

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

“…S2). Global deletion of the IP augments ischemia/reperfusion injury (19) and both global deletion of the microsomal PGE synthase enzyme (34) and CM-specific deletion of the EP4 receptor exacerbates the decline in cardiac function after experimental myocardial infarction (35). Here, deletion of CM-COX-2 resulted in interstitial and perivascular fibrosis and both features were augmented as cardiac function recovered over time following aortic banding.…”

Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice

“…Generation of cardiac myocyte-specific EP4 KO mice by a Cremediated process has been previously described (31). Genotyping and breeding details are provided in the Supplemental Data.…”

“…The cardiac function of all mice was assessed by echocardiography using an Acuson 256 system (Mountain View, CA) with a 15-MHz linear transducer, as reported previously (31). Mice were conscious during the procedure.…”

“…In this report, we characterize a new model of DCM, which develops in older mice with cardiac-specific deletion of EP4, a receptor for PGE 2 (31). Histological analysis of these mice at 10 -12 wk of age indicated that EF, myocyte cross-sectional area (MCSA), and interstitial collagen fraction (ICF) were not different from that in control littermates (WT).…”