Hydrogen Sulfide Ameliorated High Choline-Induced Cardiac Dysfunction by Inhibiting cGAS-STING-NLRP3 Inflammasome Pathway

Abstract

Although it is an essential nutrient, high choline intake directly or indirectly via its metabolite is associated with increased risk of cardiovascular disease, the mechanism of which remains to be elucidated. The present study was performed to investigate whether hydrogen sulfide (H2S) was involved in high choline-induced cardiac dysfunction and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS), the indicators of cardiac function measured by echocardiography, were significantly decreased in mice fed a diet containing 1.3% choline for 4 months as compared to the control, while applying 3,3-dimethyl-1-butanol (DMB) to suppress trimethylamine N-oxide (TMAO, a metabolite of choline) generation ameliorated the cardiac function. Subsequently, we found that feeding choline or TMAO significantly increased the protein levels of cyclic GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon genes (STING), NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β) as compared to the control, which indicated the activation of cGAS-STING-NLRP3 inflammasome axis. Moreover, the protein expression of cystathionine γ-lyase (CSE), the main enzyme for H2S production in the cardiovascular system, was significantly increased after dietary supplementation with choline, but the plasma H2S levels were significantly decreased. To observe the effect of endogenous H2S, CSE knockout (KO) mice were used, and we found that the EF, FS, and plasma H2S levels in WT mice were significantly decreased after dietary supplementation with choline, while there was no difference between CSE KO + control and CSE KO + choline group. To observe the effect of exogenous H2S, mice were intraperitoneally injected with sodium hydrosulfide (NaHS, a H2S donor) for 4 months, and we found that NaHS improved the cardiac function and reduced the protein levels of cGAS, STING, NLRP3, caspase-1, and IL-1β in mice receiving dietary choline. In conclusion, our studies revealed that high choline diet decreased plasma H2S levels and induced cardiac dysfunction via cGAS-STING-NLRP3 inflammasome axis while H2S treatment could restore the cardiac function by inhibiting cGAS-STING-NLRP3 inflammasome axis.

Hydrogen sulfide mitigates ox‑LDL‑induced NLRP3/caspase‑1/GSDMD dependent macrophage pyroptosis by S‑sulfhydrating caspase‑1

“…ox-LDL can induce DNA hypermethylation of the CSE promoter in macrophages, resulting in suppression of H 2 S production and CSE transcription, thereby exacerbating inflammatory responses ( 74 ). CSE deficiency or inhibition induces NLRP3 inflammasome activation in inflammatory cellular and mouse models with peritonitis, acute kidney injury, high choline-induced cardiac dysfunction, diabetic cardiomyopathy and colitis ( 40 , 70 , 75 – 77 ). Therefore, the present study investigated the impact of endogenous and exogenous H 2 S on macrophage pyroptosis following ox-LDL stimulation.…”

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

“…Higher H 2 S levels also enhance pathways related to oxidative stress and cell death [65]. In the analysis of the NLRP3 inflammasome in microglial cells, some studies have shown that H 2 S treatment can inhibit the activity of the NLRP3 inflammasome [66,67]. However, some studies have also shown that H2S exposure can induce the secretion of NLRP3 inflammasome-dependent IL-1β and IL-18 in human mononuclear leukocytes [68] and broiler thymocytes [69].…”

3,3-dimethyl-1-butanol and its metabolite 3,3-dimethylbutyrate ameliorate collagen-induced arthritis independent of choline trimethylamine lyase activity

“…Notably, DMBut was only present in the serum and liver of CIA mice given DMB, but not in the cecum, suggesting it is not microbially derived and lending evidence to support the absorption and metabolism of DMB within the host. Another study in male C57BL/6J mice fed a high-choline diet suggested that treatment with 1.3% (v/v) DMB reduced IL-1β protein expression in heart tissue through acting on cGAS-STING upstream of NLRP3 expression in macrophages, though this effect was attributed to the presumed inhibition of TMAO production by DMB [71]. In light of our results demonstrating that DMB is present in the host both in its native form and its fatty acid and acylcarnitine conjugates, the effect of DMB and its metabolites on in ammasome activation and IL-1β processing, independent of TMA/TMAO production, must be considered.…”