Kaempferitrin Attenuates Lipopolysaccharide-Induced Cardiac Dysfunction Through Suppression of the NF-κB/NLRP3 Signaling Pathway

Purpose: The inflammatory activation and metabolic disorders of cardiomyocytes are essential mechanisms in sepsis-related cardiac dysfunction. Kaempferitrin (Kae), a flavonoid compound, possesses various properties including anti-inflammatory and anti-glycation effects. Hence, the current study is conducted to investigate the protective effects of Kae against sepsis-induced cardiac dysfunction.

Methods: C57BL/6 J mice were treated with Kae for 2 h, followed by lipopolysaccharide (LPS) treatment. After 12 h, the echocardiographic measurements were conducted. Serum test, pathological analysis, transcriptomics, western blotting, and RT-PCR were used for exploring mechanisms. Additionally, in vitro, H9c2 and AC16 cardiomyocyte cell lines were pretreated with Kae (10 μM) for 2 h, followed by LPS stimulation (1 μg/mL).

Results: In vivo, pretreatment with Kae mitigates LPS-induced cardiac dysfunction. Kae suppresses the levels of IL-6, TNF-α, IL-1β, and IL-18 in the cardiac tissue of mice mediated by LPS. Additionally, serological and histological assessments demonstrate that Kae exhibits protective effects against LPS-induced cardiomyocyte injury and Apoptosis. Transcriptomic analysis reveals that the nuclear factor kappa-B (NF-κB)/NLRP3 signaling pathway may be a crucial mechanism. Meanwhile, it proved that LPS significantly activates NF-κB/NLRP3 to induce cardiomyocyte Pyroptosis, which is attenuated by Kae. In vitro, H9c2 and AC16 cardiomyocyte cell lines were pretreated with Kae followed by LPS stimulation, showing an inhibition of NF-κB/NLRP3 pathway, with a decreased mRNA levels of IL-6, Tnf-α, Il-1β. The NLRP3-knock out (NLRP3 ^-/- ) mice have verified that Kae ameliorating LPS-induced spetic cardiomyopathy by inhibiting NLRP3.

Conclusions: This study confirms that Kae alleviates LPS-induced left ventricular remodeling and cardiac dysfunction by suppressing the NF-κB/NLRP3/Pyroptosis pathway.

Kaempferitrin; NF‐κB signaling pathway; cardiac dysfucntion; lipopolysaccharide.