Abstract 206: Reduced Cardiac Hypertrophy, Fibrosis, Function and Activation of Stat3 in Cardiac-Specific EP4 Receptor Knock-Out Mice Following Myocardial Infarction
We have previously shown that:
COX-2 inhibition reduces cardiac hypertrophy (CH) and fibrosis post myocardial infarction (MI) in a mouse model; and
PGE2 stimulates cardiomyocyte hypertrophy in vitro via its EP4 receptor.
To test the role of EP4 in CH in vivo, we generated mice lacking EP4 only in cardiac myocytes (CM-EP4 KO). This deletion did not affect cardiac function (CF) and CH in normal/unstressed conditions. MI was induced in 12–13 week old male mice by ligating the left anterior descending coronary artery. Two weeks later, the mice were subjected to echocardiography to assess CF and histology to assess CH and fibrosis (Table 1⇓). There was no difference in infarct size (IS) between CM-EP4 KO mice and littermate controls. Following MI, CM-EP4 KO mice showed less CH (myocyte cross-sectional area, MCSA; diastolic posterior wall thickness, PWTd) and fibrosis (interstitial collagen fraction, ICF) than controls with MI. PWTd increased in the control but not in the CM-EP4 KO mice. Also, CM-EP4 KO mice had reduced ejection fraction (EF) and shortening fraction (SF) and increased systolic left ventricular dimension (LVDs) compared with controls. The transcription factor Stat3 is involved in hypertrophy and protection from ischemic injury. Western blot indicated that Stat3 was activated 1.8 ± 0.3 fold in control hearts (n =6) but totally eliminated in CM-EP4 KO hearts (p <0.05). Thus, CM-EP4 deletion decreased CH and fibrosis. However, CF was unexpectedly worsened in these mice. We conclude that cardiac myocyte EP4 plays a role in compensatory CH via activation of Stat3. EP4 may also play a role in systolic function..