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Hydrogen sulfide ameliorates hypoxic pulmonary hypertension in rats by inhibiting aerobic glycolysis-pyroptosis

CHENG Yuan¹, TIAN Yun-Na¹, HUANG Man¹, XU Jun-Peng¹, CAO Wen-Jie¹, JIA Xu-Guang², YOU Li-Yi³, WANG Wan-Tie^1,*

¹Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou 325035, China；²College of Physical Education and Health, Yibin University, Yibin 644000, China；³Department of Ultrasound, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou 325400, China

Abstract

The present study aimed to explore whether hydrogen sulfide (H2S) improved hypoxic pulmonary hypertension (HPH) in rats by inhibiting aerobic glycolysis-pyroptosis. Male Sprague-Dawley (SD) rats were randomly divided into normal group, normal+ NaHS group, hypoxia group, and hypoxia+NaHS group, with 6 rats in each group. The control group rats were placed in a normoxic (21% O2) environment and received daily intraperitoneal injections of an equal volume of normal saline. The normal+NaHS group rats were placed in a normoxic environment and intraperitoneally injected with 14 μmol/kg NaHS daily. The hypoxia group rats were placed in a hypoxia chamber, and the oxygen controller inside the chamber maintained the oxygen concentration at 9% to 10% by controlling the N2 flow rate. An equal volume of normal saline was injected intraperitoneally every day. The hypoxia+NaHS group rats were also placed in an hypoxia chamber and intraperitoneally injected with 14 μmol/kg NaHS daily. After the completion of the four-week modeling, the mean pulmonary artery pressure (mPAP) of each group was measured using right heart catheterization technique, and the right ventricular hypertrophy index (RVHI) was weighed and calculated. HE staining was used to observe pathological changes in lung tissue, Masson staining was used to observe fibrosis of lung tissue, and Western blot was used to detect protein expression levels of hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate kinase isozyme type M2 (PKM2), nucleotidebinding oligomerization domain-like receptor protein 3 (NLRP3), GSDMD-N-terminal domain (GSDMD-N), Caspase-1, interleukin- 1β (IL-1β) and IL-18 in lung tissue. ELISA was used to detect contents of IL-1β and IL-18 in lung tissue. The results showed that, compared with the normal control group, there were no significant changes in all indexes in the normal+NaHS group, while the hypoxia group exhibited significantly increased mPAP and RVHI, thickened pulmonary vascular wall, narrowed lumen, increased collagen fibers, up-regulated expression levels of aerobic glycolysis-related proteins (HK2 and PKM2), up-regulated expression levels of pyroptosis-related proteins (NLRP3, GSDMD-N, Caspase-1, IL-1β, and IL-18), and increased contents of IL-1β and IL-18. These changes of the above indexes in the hypoxia group were significantly reversed by NaHS. These results suggest that H2S can improve rat HPH by inhibiting aerobic glycolysis-pyroptosis.

Key words: hydrogen sulfide; pulmonary hypertension; glycolysis; pyroptosis; hypoxia

Received: 　　Accepted:

Corresponding author: 王万铁　　E-mail:

DOI: 10.13294/j.aps.2025.0015

Citing This Article：

CHENG Yuan, TIAN Yun-Na, HUANG Man, XU Jun-Peng, CAO Wen-Jie, JIA Xu-Guang, YOU Li-Yi, WANG Wan-Tie. Hydrogen sulfide ameliorates hypoxic pulmonary hypertension in rats by inhibiting aerobic glycolysis-pyroptosis. Acta Physiol Sin 2025; 77 (3): 465-471 (in Chinese with English abstract).