VITAMIN D DEFICIENCY AGGRAVATES MYOCARDIAL PYROPTOSIS INJURY BY ACTIVATING NOX4/NLRP3 INFLAMMASOME PATHWAY IN DIABETIC MICE

SUN Zhen; MA Yu-xia; WANG Le; LIU Gang; WANG Dong-xia

PDF(9444 KB)

Acta Nutrimenta Sinica ›› 2025, Vol. 47 ›› Issue (3) : 263-269.

VITAMIN D DEFICIENCY AGGRAVATES MYOCARDIAL PYROPTOSIS INJURY BY ACTIVATING NOX4/NLRP3 INFLAMMASOME PATHWAY IN DIABETIC MICE

SUN Zhen¹, MA Yu-xia², WANG Le¹, LIU Gang¹, WANG Dong-xia²

Author information +

History +

Abstract

Objective To investigate the mechanisms through which vitamin D (VD) deficiency exacerbates myocardial injury in diabetic mice. Methods Male 6-week-old db/m and db/db mice were randomly divided into four groups based on body weight and fasting blood glucose levels (n=8 per group): control group (Con), vitamin D deficiency control group (def-Con), model group (DM), and vitamin D deficiency model group (def-DM). All mice were fed for a duration of 17 weeks, with the def-Con and def-DM groups mice receiving a vitamin D-deficient diet. Serum glucose, lipid profiles, and CK-MB levels were measured. Myocardial histopathological changes were detected using HE staining. Cardiac function was assessed via echocardiography. Protein expression levels associated with the NOX4/NLRP3 inflammasome pathway and pyroptosis in cardiac tissue were determined by Western blotting. Results Compared with the Con group, DM mice exhibited significant increases in body weight and food intake, alongside notable reductions in the heart weight/body weight ratio, and elevated serum glucose and lipid levels (P<0.05). Moreover, compared to the DM group, the def-DM group displayed further increases in body weight and food intake, additional reductions in the heart weight/body weight ratio, and higher serum lipid levels (P<0.05), with no significant disparity in serum glucose levels (P>0.05). Cardiomyocyte hypertrophy was significantly pronounced in the DM group when compared to the Con group, accompanied by substantial reductions in cardiac LVEF and LVFS (P<0.05). The def-DM group displayed exacerbated cardiomyocyte hypertrophy and decreased cardiac LVEF and LVFS when compared to the DM group (P<0.05). Notably, the expression levels of NOX4/NLRP3 inflammasome and pyroptosis-related proteins were significantly elevated in the cardiac tissues of mice in the DM group compared to the Con group (P<0.05). Furthermore, the def-DM group presented further elevation in the expression levels of these proteins in cardiac tissues compared to the DM group (P<0.05). Conclusion Vitamin D deficiency may aggravate myocardial pyroptosis injury in diabetic mice by activating the NOX4/NLRP3 inflammasome pathway.

Key words

vitamin D deficiency / myocardial injury in diabetic mice / NLRP3 inflammasome / pyroptosis

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

SUN Zhen, MA Yu-xia, WANG Le, LIU Gang, WANG Dong-xia. VITAMIN D DEFICIENCY AGGRAVATES MYOCARDIAL PYROPTOSIS INJURY BY ACTIVATING NOX4/NLRP3 INFLAMMASOME PATHWAY IN DIABETIC MICE[J]. Acta Nutrimenta Sinica. 2025, 47(3): 263-269

References

[1] Grubic RP, Planinic Z, Liberati PA, et al. The mystery of diabetic cardiomyopathy: from early concepts and underlying mechanisms to novel therapeutic possibili-ties[J]. Int J Mol Sci, 2021, 22: 5973.
[2] Dandamudi S, Slusser J, Mahoney DW, et al. The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota[J]. J Card Fail, 2014, 20: 304–309.
[3] Liu P, Zhang Z, Chen H, et al. Pyroptosis: mechanisms and links with diabetic cardiomyopathy[J]. Ageing Res Rev, 2024, 94: 102182.
[4] Zhong C, Xie Y, Wang H, et al, Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy[J]. Eur J Pharmacol, 2024, 964: 176253.
[5] Gao G, Fu L, Xu Y, et al. Cyclovirobuxine D ameliorates experimental diabetic cardiomyopathy by inhibiting cardiomyocyte pyroptosis via NLRP3 in vivo and in vitro[J]. Front Pharmacol, 2022, 13: 906548.
[6] Burgoyne JR, Mongue-Din H, Eaton P, et al. Redox signaling in cardiac physiology and pathology[J]. Circ Res, 2012, 111: 1091–1106.
[7] Liu R, Duan T, Yu L, et al. Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis[J]. Cardiovasc Diabetol,2023, 22: 25.
[8] Fan L, Xiao Q, Zhang L, et al. CAPE-pNO2 attenuates diabetic cardiomyopathy through the NOX4/NF-κB pathway in STZ-induced diabetic mice[J]. Biomed Pharmacother, 2018, 108: 1640–1650.
[9] Li XX, Ling SK, Hu MY, et al. Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome pathway in diabetic rats[J]. Free Radic Biol Med, 2019, 145: 175–186.
[10] Pan LL, Ren Z, Liu Y, et al. A novel danshensu derivative ameliorates experimental colitis by modulating NADPH oxidase 4-dependent NLRP3 inflammasome activation[J]. J Cell Mol Med, 2020, 24: 12955–12969.
[11] Wang R, Li L, Wang B.Poncirin ameliorates oxygen glucose deprivation/reperfusion injury in cortical neurons via inhibiting NOX4-mediated NLRP3 inflammasome activation[J]. Int Immunopharmacol, 2022, 102: 107210.
[12] Holick MF.The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention[J]. Rev Endocr Metab Disord, 2017, 18: 153–165.
[13] Yakout SM, Alfadul H, Ansari M, et al. Vitamin D status modestly regulates NOD-like receptor family with a pyrin domain 3 inflammasome and interleukin profiles among Arab adults[J]. Int J Mol Sci, 2023, 24: 16377.
[14] 潘丽莎,华美云,徐思雅,等. 维生素D对急性肝衰竭小鼠肝脏的保护作用[J]. 中华肝脏病杂志, 2021, 29: 545–550.
[15] Wang D, Li Y, Wang N, et al. 1α,25-Dihydroxyvitamin D₃ prevents renal oxidative damage via the PARP1/ SIRT1/NOX4 pathway in Zucker diabetic fatty rats[J]. Am J Physiol Endocrinol Metab, 2020, 318: E343–E356.
[16] Manna P, Achari AE, Jain SK.Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1/ AMPK/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice[J]. Arch Biochem Biophys, 2017, 615: 22–34.
[17] Lorenzo-Almoros A, Tunon J, Orejas M, et al, Diagnostic approaches for diabetic cardiomyopathy[J]. Cardiovasc Diabetol, 2017, 16: 28.
[18] Abukhalil MH, Althunibat OY, Aladaileh SH, et al. Galangin attenuates diabetic cardiomyopathy through modulating oxidative stress, inflammation and apoptosis in rats[J]. Biomed Pharmacother, 2021, 138: 111410.
[19] Zhang P, Guo D, Xu B, et al. Association of serum 25-hydroxyvitamin D with cardiovascular outcomes and all-cause mortality in individuals with prediabetes and diabetes: results from the UK biobank prospective cohort study[J]. Diabetes Care, 2022, 45: 1219–1229.
[20] Jayedi A, Daneshvar M, Jibril AT, et al. Serum 25(OH)D concentration, vitamin D supplementation, and risk ofcardiovascular disease and mortality in patients with type 2 diabetes or prediabetes: a systematic review and dose-response meta-analysis[J]. Am J Clin Nutr, 2023, 118: 697–707.
[21] Assalin HB, Rafacho BP, Dos Santos PP, et al. Impact of the length of vitamin D deficiency on cardiac remodeling[J]. Circ Heart Fail, 2013, 6: 809–816.
[22] Lee H, Lee H, Lim Y.Vitamin D3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice[J]. Nutr Res, 2020, 80: 55–65.
[23] Chen H, Zhang Y, Miao Y, et al. Vitamin D inhibits ferroptosis and mitigates the kidney injury of prediabetic mice by activating the Klotho/p53 signaling pathway[J]. Apoptosis, 2024, 29: 1780–1792.
[24] Guo X, Lin H, Liu J, et al. 1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation[J]. J Nutr Biochem, 2020, 80: 108380.
[25] Qu H, Lin K, Wang H, et al. 1,25(OH)₂D₃ improves cardiac dysfunction, hypertrophy, and fibrosis through PARP1/SIRT1/mTOR-related mechanisms in type 1 diabetes[J]. Mol Nutr Food Res, 2017, 61: 1600338.
[26] Thaik CM, Calderone A, Takahashi N, et al. Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes[J]. J Clin Invest, 1995, 96: 1093–1099.
[27] Wei H, Qu H, Wang H, et al. 1,25-Dihydroxyvitamin D3 prevents the development of diabetic cardiomyopathy in type 1 diabetic rats by enhancing autophagy via inhibiting the β-catenin/TCF4/GSK-3β/mTOR pathway[J]. J Steroid Biochem Mol Biol, 2017, 168: 71–90.
[28] Toldo S, Mezzaroma E, Buckley LF, et al. Targeting the NLRP3 inflammasome in cardiovascular diseases[J]. Pharmacol Ther, 2022, 236: 108053.
[29] Wang G, Ma TY, Huang K, et al. Role of pyroptosis in diabetic cardiomyopathy: an updated review[J]. Front Endocrinol (Lausanne), 2023, 14: 1322907.
[30] Luo B, Huang F, Liu Y, et al. NLRP3 Inflammasome as a molecular marker in diabetic cardiomyopathy[J]. Front Physiol, 2017, 8: 519.