Pretreatment with Indole-3-Propionic Acid Attenuates Lipopolysaccharide-Induced Cardiac Dysfunction and Inflammation Through the AhR/ NF-κB/NLRP3 Pathway

Background: Patients with sepsis frequently develop septic cardiomyopathy, which is known to be closely related to excessive inflammatory responses. Indole-3-propionic acid (IPA) is a tryptophan metabolite with anti-inflammatory properties that have been demonstrated in various studies. In this study, we investigated the underlying mechanisms and therapeutic role of IPA in septic cardiomyopathy. Methods: To investigate the role of IPA in septic cardiomyopathy, we constructed a lipopolysaccharide (LPS)-induced rat model of septic cardiomyopathy, and treated rats with IPA. Inflammatory factors and the NF-κB/NLRP3 pathway were evaluated in myocardial tissues and cells after IPA treatment using RT-qPCR, ELISA, Western blotting, and immunohistochemistry. To further elucidate the role of the aryl hydrocarbon receptor (AhR), we detected changes in inflammatory mediators and the NF-κB/NLRP3 pathway in in vivo and in vitro models of septic cardiomyopathy, which were treated with the AhR antagonist CH-223191 and/or AhR agonist FICZ. Results: IPA supplementation improved cardiac dysfunction in rats with septic cardiomyopathy. IPA reduced inflammatory cytokine release and inhibited NF-κB/NLRP3 signaling pathway in myocardial tissue and in H9c2 cells. CH-223191 impaired the antiinflammatory effect of IPA in LPS-treated cells, whereas FICZ exerted the same effect as IPA. IPA also exhibited antiinflammatory activity by binding to the AhR. Our results indicated that IPA attenuated septic cardiomyopathy in rats via AhR/NF-κB/NLRP3 signaling. Conclusion: Our study revealed that IPA improved left heart dysfunction and myocardial inflammation caused by sepsis via AhR/NF-κB/NLRP3 signaling, suggesting that IPA is a potential therapy for septic cardiomyopathy.