Abstract 948: Pharmacological Activation of the Prostanoid Receptor EP4 Improves Cardiac Function after Myocardial Ischemia/Reperfusion Injury
Background: Increased expression of Prostaglandin E2 (PGE2) has recently been described in clinical and experimental myocardial ischemia/reperfusion (I/R) injury. EP4, one of the PGE2 receptor subtypes, has been reported to be expressed in the inflammatory areas in the hearts. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether activation of the EP4 suppresses myocardial I/R injury.
Methods and Results: To test the hypothesis that EP4-selective agonist (EP4RAG) can attenuate left ventricular remodeling after I/R injury, we subcutaneously injected EP4RAG (3mg/kg, n=6) or PBS (n=8) to rats with I/R injury. After 7 days of reperfusion, I/R rats exerted left ventricular dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis, and MCP-1 protein levels were increased in both nonischemic zone and ischemic myocardium. The EP4RAG treatment significantly reduced infarction area/area at risk (PBS 72.4+/−0.7 vs. EP4RAG 23.3+/−0.6 %; P<0.05) and improved LVFS (PBS 23.8+/−1.4 vs. EP4RAG 48.5+/−2.4 %; P<0.05). The EP4RAG also attenuated recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis detected by immunohistochemical studies. Western blot analysis and RNase protection assay showed EP4RAG reduced the level of MCP-1 protein, myocardial gene expression of TNF-alpha, IL-6, and IL-1beta. Although I/R resulted in left ventricular fibrosis with increasing the MMP-2 and -9 activities, gelatin zymography revealed EP4RAG significantly reduced these changes. Chemoattractant assay revealed that this EP4RAG also suppressed the migration of macrophages stimulated by IL-1beta (number of cells in HPF, PBS 109.6+/−9.2 vs. EP4RAG 24.6+/−2.2 counts; P<0.05) and decreased the level of MCP-1 protein in vitro (PBS 587.3+/−55.3 vs. EP4RAG 171.5+/−47.5 pg/mL; P<0.05).
Conclusions: The EP4RAG is effective for prevention of ventricular remodeling after I/R injury by suppressing the infiltration of inflammatory cells, especially macrophages, and macrophage-derived MCP-1.