Reduced cardiac remodeling and function in cardiac-specific EP4 receptor knockout mice with myocardial infarction.
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.
Qian
Jian-Yong
JY
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689, USA.
Harding
Pamela
P
Liu
Yunhe
Y
Shesely
Ed
E
Yang
Xiao-Ping
XP
LaPointe
Margot C
MC
D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000517:prevention & control; D004452:Echocardiography; D005355:Fibrosis; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000172:deficiency*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013318:Stroke Volume; D020257:Ventricular Remodeling
C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020097:Natriuretic Peptide, Brain