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Hydrogen Sulfide Improves Outcomes in a Murine Model of Necrotizing Enterocolitis via the Cys440 Residue on Endothelial Nitric Oxide Synthase

Background: Hydrogen sulfide (H2S) has been shown to improve outcomes in a murine model of necrotizing enterocolitis (NEC). There is evidence in humans that H2S relies on endothelial nitric oxide synthase (eNOS) to exert its protective effects, potentially through the persulfidation of eNOS at the Cysteine 443 residue. We obtained a novel mouse strain with a mutation at this residue (eNOSC440G) and hypothesized that this locus would be critical for GYY4137 (an H2S donor) to exert its protective effects.

Methods: Necrotizing enterocolitis was induced in 5-day old wild type (WT) and eNOSC440G mice using intermittent exposure to hypoxia and hypothermia in addition to gavage formula feeds. On postnatal day 9, mice were humanely euthanized. Data collected included daily weights, clinical sickness scores, histologic lung injury, intestinal injury (macroscopically and histologically), and intestinal perfusion. During the NEC model, pups received daily intraperitoneal injections of either GYY4137 (50 mg/kg) or PBS (vehicle). Data were tested for normality and compared using t-test or Mann-Whitney, and a p-value <0.05 was considered significant.

Results: In WT mice, the administration of GYY4137 significantly improved clinical sickness scores, attenuated intestinal and lung injury, and improved mesenteric perfusion compared to vehicle (p < 0.05). In eNOSC440G mice, the treatment and vehicle groups had similar clinical sickness scores, intestinal and lung injury scores, and intestinal perfusion.

Conclusions: GYY4137 administration improves clinical outcomes, attenuates intestinal and lung injury, and improves perfusion in a murine model of necrotizing enterocolitis. The beneficial effects of GYY4137 are dependent on the Cys440 residue of eNOS.

 

Comments:

The study you described investigates the role of hydrogen sulfide (H2S) in a murine model of necrotizing enterocolitis (NEC) and its dependence on endothelial nitric oxide synthase (eNOS) and a specific mutation in eNOS (eNOSC440G). Here's a breakdown of the key findings and conclusions:

1. **Background**: NEC is a serious gastrointestinal disease in infants, and H2S has previously shown promise in improving outcomes in a murine model of NEC. The study aims to understand the mechanism by which H2S exerts its protective effects, particularly focusing on eNOS and the Cysteine 440 residue.

2. **Methods**: NEC was induced in both wild-type (WT) mice and mice with the eNOSC440G mutation using a combination of hypoxia, hypothermia, and gavage formula feeds. The mice were divided into groups receiving either GYY4137 (an H2S donor) or a control (PBS) via intraperitoneal injections. Various parameters, including weight, clinical scores, lung and intestinal injury, and intestinal perfusion, were assessed. Statistical tests (t-test or Mann-Whitney) were used to compare the data.

3. **Results**:
   - In WT mice treated with GYY4137:
     - Clinical sickness scores improved.
     - Intestinal and lung injury scores were attenuated.
     - Mesenteric perfusion was improved.
     - These effects were statistically significant (p < 0.05).

- In eNOSC440G mice treated with GYY4137:
     - Clinical sickness scores, intestinal and lung injury scores, and intestinal perfusion were similar to the vehicle group.
     - GYY4137 did not exert significant protective effects in these mice.

4. **Conclusions**:
   - The study confirms that GYY4137 administration has protective effects in a murine model of NEC, improving clinical outcomes, attenuating intestinal and lung injury, and enhancing perfusion.
   - Importantly, these beneficial effects of GYY4137 appear to be dependent on the presence of the Cysteine 440 residue in eNOS. In eNOSC440G mice, which have a mutation at this residue, GYY4137 did not provide the same protective benefits observed in WT mice.
  
In summary, this research suggests that H2S, delivered through GYY4137, has a protective role in NEC in mice. However, this protection relies on the presence of the Cys440 residue in eNOS. These findings contribute to our understanding of the mechanisms involved in NEC pathogenesis and the potential therapeutic benefits of H2S in this context.

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S9920 GYY4137 GYY4137 is a novel, water-soluble hydrogen sulfide (H2S)–releasing molecule with vasodilator and antihypertensive activity. GYY4137 shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway. GYY4137 also shows anti-inflammatory activity.

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