Targeting PGE2 to treat sepsis-induced acute heart failure

Richard Schell (Heidelberg)1, B. G. Niehaus (Heidelberg)2, F. Alban (Heidelberg)1, N. Frey (Heidelberg)1, J. Backs (Heidelberg)2

1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Innere Medizin VIII, Institut für Experimentelle Kardiologie Heidelberg, Deutschland



Recently, we uncovered a previously unknown link between inflammation and sepsis-induced acute heart failure and demonstrated that prostaglandin E2 led to disinhibition of the transcription factor MEF2 via the EP3 receptor. On the basis of these findings, we investigated the impact of pharmacological nonselective inhibition of cyclooxygenase with acetylsalicylic acid and direct inhibition of the EP3 receptor on cardiac function in a model of lipopolysaccharide-induced acute heart failure. 


8-week-old Balbc wild-type mice were treated for 6 days with the selective EP3 inhibitor L798106. On day 6, we administered either 7 mg/kg bw lipopolysaccharide or sodium chloride solution intraperitoneally to induce sepsis. We found that septic mice treated with L798106 showed a significantly increased ejection fraction after 24h compared to sham-treated littermates (48% vs 63%, p=0.003). Next, we investigated the effects of unselective inhibition of cyclooxygenase I and II via administration of acetylsalicylic acid on the cardiac function of septic mice. ASA was intravenously injected 1 hour prior to sepsis induction by intraperitoneal application of 7 mg/kg bw LPS. ASA-treated mice showed a significantly increased ejection fraction at 8h (24% vs 34%, p=0,0001) and 24h (36% vs 48%, p= 0,0082) compared to their sham-treated littermates. Measurement of PGE2-levels by mass spectrometry showed nearly abolished levels of PGE2 in heart tissue of mice pretreated with ASA and higher PGE2-levels in heart tissue of sham-treated littermates strongly correlated with reduced ejection fraction. Further and unbiased investigation with RNA-Seq revealed a relevant overlap of inflammation-induced and ASA-diminished genes with annotated MEF2D-genes, proving that targeting PGE2-dependent signaling pathways leads to reduced activity of MEF2 and subsequent improved left ventricular function. 


The evidence presented here suggests an important role of the inflammatory mediator PGE2 in sepsis-induced acute heart failure. Therefore targeting of PGE2 either by inhibiting formation or blocking specifically the EP3-receptor could be a potential therapeutic strategy for septic cardiomyopathy. To further investigate our findings we currently perform comprehensive sequencing-analysis in heart tissue of pharmacologically treated septic mice to hereby deepen our understanding of the underlying molecular mechanisms.
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