Vitamin D improves diabetic cardiomyopathy by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway

Dongxia Wang; Zhen Sun; Huaxing Zhang; Jingyi Xiang; Honghui Wu; Congcong Lu; Mengyue Li; Yuxia Ma; Gang Liu; Le Wang

doi:10.1039/D5FO00717H

Vitamin D improves diabetic cardiomyopathy by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway†

Dongxia Wang,

‡*^a Zhen Sun,‡^b Huaxing Zhang,^c Jingyi Xiang,^b Honghui Wu,^a Congcong Lu,^d Mengyue Li,^a Yuxia Ma,

^a Gang Liu^b and Le Wang*^b

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* Corresponding authors

^a Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang 050017, China
E-mail: wangdx@hebmu.edu.cn

^b Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang 050000, China
E-mail: wangle@hebmu.edu.cn

^c Core Facilities and Centers, Hebei Medical University, Shijiazhuang 050017, Hebei, China

^d Department of Pathology, Hebei Medical University, Shijiazhuang 050017, Hebei, China

Abstract

Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus, for which effective treatment options remain unavailable. Recent studies have demonstrated that vitamin D exerts protective effects against DCM, but its role in alleviating cellular pyroptosis remains uncertain. The present study aimed to investigate the ameliorative effects of vitamin D on pyroptosis in DCM and to elucidate the underlying molecular mechanisms. In the in vivo experiments, male diabetic db/db mice were treated with or without 1,25(OH)₂D₃ by oral gavage for 17 weeks, while age-matched non-diabetic db/m mice served as control group. In the in vitro experiments, H9c2 cardiomyocytes were exposed to normal glucose or high glucose and palmitic acid environment with or without 1,25(OH)₂D₃ treatment for 24 h. The results revealed that 1,25(OH)₂D₃ treatment significantly reduced body mass, food intake, water intake, and urine volume in db/db mice. Additionally, it improved fasting serum glucose levels, urine glucose levels, and glucose tolerance, while also enhancing insulin sensitivity and ameliorating dyslipidemia. Furthermore, 1,25(OH)₂D₃ alleviated myocardial hypertrophy, restored ultrastructural changes in cardiomyocytes, and improved cardiac systolic and diastolic functions. Both the in vivo and in vitro experiments showed that 1,25(OH)₂D₃ significantly downregulated the expression of proteins related to the NOX4/NLRP3 inflammasome pathway and pyroptosis. Specifically, in the in vivo models, 1,25(OH)₂D₃ effectively decreased the expression of genes linked to these pathways. In conclusion, this study provides evidence that vitamin D may improve DCM by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway. These findings highlight the therapeutic potential of vitamin D in managing DCM and underscore the importance of targeting pyroptosis.

Food & Function

Vitamin D improves diabetic cardiomyopathy by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway†

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Vitamin D improves diabetic cardiomyopathy by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway

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