Indole-3-propionic acid improves cardiac function in septic cardiomyopathy through the AhR/NF-κB/NLRP3 pathway

Abstract

Abstract Background Sepsis patients frequently develop septic cardiomyopathy. It is well known that sepsis-induced cardiomyopathy is closely related to excess inflammatory responses. Indole-3-propionic acid (IPA) is a tryptophan metabolite that has anti-inflammatory properties in many different diseases. In our research, we investigated IPA's underlying mechanisms and therapeutic role in septic cardiomyopathy. Methods To investigate IPA’s role in septic cardiomyopathy, a lipopolysaccharide (LPS)-induced rat model of septic cardiomyopathy was constructed, and rats were treated with IPA. Inflammatory factors and the NF-kB/NLRP3 pathway were evaluated in myocardial tissues and cells after the IPA treatment using RT-qPCR, ELISA, Western blot, and immunohistochemistry. To elucidate the role of the aryl hydrocarbon receptor (AhR), we detected the changes of inflammatory mediators and the NF-κB/NLRP3 pathway in cardiomyocytes treated by CH-223191 and FICZ. Results IPA supplementation improved cardiac dysfunction in septic cardiomyopathy rats. IPA reduced inflammatory cytokine release and inhibited NF-κB/NLRP3 signaling activity in myocardial tissue and in H9c2 cells. We found that CH-223191 blocked IPA's anti-inflammatory effect in LPS-treated cells, while FICZ exerted the same effect as IPA. We further found that IPA exhibited anti-inflammatory effects through binding to AhR. Our results indicated that IPA attenuated septic cardiomyopathy in rats via the AhR/NF-κB/NLRP3 signaling. Conclusion The study found that IPA improved left heart dysfunction and myocardial inflammation caused by sepsis via the AhR/NF-κB/NLRP3 signaling. This suggested that IPA could be a potential therapy for septic cardiomyopathy.