Reduced hydrogen sulfide production contributes to adrenal insufficiency induced by hypoxia via modulation of NLRP3 inflammasome activation

Ningning Zhang; Zhan Zhou; Yan Huang; Gang Wang; Zhengshan Tang; Jianqiang Lu; Changnan Wang; Xin Ni

doi:10.1080/13510002.2022.2163354

Reduced hydrogen sulfide production contributes to adrenal insufficiency induced by hypoxia via modulation of NLRP3 inflammasome activation

Redox Rep. 2023 Dec;28(1):2163354. doi: 10.1080/13510002.2022.2163354.

Authors

Ningning Zhang^{1

2

3}, Zhan Zhou^{1

2}, Yan Huang³, Gang Wang³, Zhengshan Tang^{1

2}, Jianqiang Lu⁴, Changnan Wang³, Xin Ni^{1

2

3}

Affiliations

¹ National Clinical Research Center for Geriatric Disorders, Central South University Xiangya Hospital, Changsha, People's Republic of China.
² International Collaborative Research Center for Medical Metabolomics, Central South University Xiangya Hospital, Changsha, People's Republic of China.
³ Department of Physiology, Navy Medical University, Shanghai, People's Republic of China.
⁴ The Key Laboratory of Exercise and Health Sciences of Ministry of Education, School of Kinesiology, Shanghai University of Sport, Shanghai, People's Republic of China.

Abstract

Objective: Adrenocortical responsiveness is critical for maintaining glucocorticoids production and homeostasis during stress. We sought to investigate adrenocortical responsiveness during hypoxia in mice and the mechanisms responsible for the regulation of adrenal responsiveness.Methods: (1) Adult male WT mice were randomly divided into four groups: normoxia, hypoxia (24h), hypoxia (72h), hypoxia (72h) + GYY4137(hydrogen sulfide (H₂S) donor, 133mmol/kg/day); (2) WT mice were randomly divided into four groups: sham, adrenalectomy (ADX), sham+hypoxia, ADX+hypoxia; (3) Cse^-/- mice were randomly divided into two groups: Cse^-/-, Cse^-/- +GYY4137.Results: The circulatory level of corticosteroid induced by ACTH stimulation was significantly reduced in the mice with hypoxia compared with control mice. The mortality rate induced by lipopolysaccharide (LPS) increased during hypoxia. Cystathionine-γ-lyase (CSE) expression was significantly reduced in adrenal glands during hypoxia. GYY4137 treatment significantly increased adrenal responsiveness and attenuated NLRP3 inflammasome activation in mice treated by hypoxia and Cse^-/- mice. Furthermore, The sulfhydrated level of PSMA7 in adrenal gland was decreased in the mice with hypoxia and Cse^-/- mice. PSMA7 was S-sulfhydrated at cysteine 70. Blockage of S-sulfhydration of PSMA7 increased NLRP3 expression in adrenocortical cells.Conclusion: Reduced H₂S production mediated hypo-adrenocortical responsiveness and NLRP3 inflammasome activation via PAMA7 S-sulfhydration during hypoxia.

Keywords: Hydrogen sulfide; NLRP3; adrenal insufficiency; hypoxia; inflammasome.

MeSH terms

Adrenal Insufficiency*
Animals
Hydrogen Sulfide* / metabolism
Hydrogen Sulfide* / pharmacology
Hypoxia
Inflammasomes
Male
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
Sulfides / pharmacology

Substances

Hydrogen Sulfide
GYY 4137
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Sulfides
Nlrp3 protein, mouse

Grants and funding

This work was supported by grants from the Natural Science Foundation of China (31971102) and Hunan Provincial Science and Technology Department (2018RS3030).