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Hydrogen Sulfide Ameliorated High Choline-Induced Cardiac Dysfunction by Inhibiting cGAS-STING-NLRP3 Inflammasome
Lu Bai1, Jing Dai2, Yuxuan Xia1
1Department of Physiology, Hebei Medical University, Hebei 050017, China.
Insights
High choline intake impairs heart function by reducing hydrogen sulfide (H2S) and activating the cGAS-STING-NLRP3 inflammasome axis. Supplementation with H2S protects against this choline-induced cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease
- Inflammation Research
Background:
- High choline intake is linked to cardiovascular disease, but the underlying mechanisms are unclear.
- Trimethylamine N-oxide (TMAO) is a choline metabolite implicated in cardiovascular risk.
- Hydrogen sulfide (H2S) plays a role in cardiovascular health, but its involvement in choline-induced dysfunction needs investigation.
Purpose of the Study:
- To investigate the role of hydrogen sulfide (H2S) in high choline-induced cardiac dysfunction.
- To elucidate the molecular mechanisms linking high choline intake to heart problems.
- To explore the therapeutic potential of H2S in mitigating choline-related cardiac damage.
Main Methods:
- Mice were fed a high-choline diet for 4 months, with some receiving DMB to inhibit TMAO production or NaHS as an H2S donor.
- Echocardiography was used to assess cardiac function (ejection fraction and fractional shortening).
- Western blotting and ELISA were employed to measure protein levels of key inflammatory markers (cGAS, STING, NLRP3, caspase-1, IL-1β) and H2S-producing enzymes (CSE).
Main Results:
- High choline diet significantly reduced cardiac function (EF, FS) in mice.
- Choline or TMAO feeding increased the expression of cGAS, STING, NLRP3, caspase-1, and IL-1β, indicating inflammasome activation.
- Dietary choline decreased plasma H2S levels and increased CSE expression, while H2S supplementation (NaHS) improved cardiac function and reduced inflammasome markers.
Conclusions:
- High choline intake induces cardiac dysfunction by decreasing plasma H2S levels and activating the cGAS-STING-NLRP3 inflammasome axis.
- H2S plays a protective role against high choline-induced cardiac dysfunction.
- H2S treatment can restore cardiac function by inhibiting the 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.
