Dysregulated ApoD Glycosylation Fuels Inflammation-Calcification Coupling in Aortic Valve Disease
摘要
Calcific aortic valve disease(CAVD)affects more than 5%of individuals over 65 years,yet no pharmacological therapy exists to halt its progression.Inflammation and lipid deposition are known drivers,but the molecular links between these processes remain incompletely defined.Here we show that glycosylation-related enzymes are dysregulated in human calcified valves based on bioinformatics analysis of public datasets(GSE12644).We identified MGAT3,FUT8,and B3GNT2 as key enzymes significantly downregulated in CAVD,with MGAT3 showing a logFC of-1.59(adj.P = 0.0336),FUT8 showing a logFC of-2.25(adj.P = 0.0443),and B3GNT2 showing a logFC of-4.43(adj.P = 0.0336).These enzymes are enriched in N-glycan biosynthesis and inflammatory pathways.Correlation analysis revealed that these enzymes are significantly associated with immune cell infiltration,particularly macrophages.Our findings suggest that dysregulated glycosylation of ApoD may contribute to CAVD pathogenesis through modulating the inflammatory microenvironment,and identify glycosylation enzymes as potential diagnostic biomarkers for this intractable disease.
参考文献
Lindman, B. R. et al. Calcific aortic stenosis. Nat. Rev. Dis. Primers 2, 16006 (2016).
Osnabrugge, R. L. et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement. J. Am. Coll. Cardiol. 62, 1002-1012 (2013).
Pawade, T. A., Newby, D. E. & Dweck, M. R. Calcification in aortic stenosis: the skeleton key. J. Am. Coll. Cardiol. 66, 561-577 (2015).
lung, B. & Vahanian, A. Epidemiology of valvular heart disease in the adult. Nat. Rev. Cardiol. 8, 162-172 (2011).
Mathieu, P., Bouchareb, R. & Boulanger, M. C. Innate and adaptive immunity in calcific aortic valve disease. J. Immunol. Res. 2015, 851945 (2015).
Zheng, K. H. et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J. Am. Coll. Cardiol. 73, 2150-2162 (2019).
Tengesdal, I. W. et al. Targeting the NLRP3 inflammasome in cardiovascular disease. Nat. Rev. Cardiol. 19, 334-348 (2022).
Rassart, E., Desmarais, F., Najyb, O., Bergeron, K. F. & Mounier, C. Apolipoprotein D. Gene 756, 144874 (2020).
Bhatia, S. et al. Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D. Biochemistry 51, 51-61 (2012).
Wang, Y. et al. Hypoglycosylated ApoD protects the blood-brain barrier via CD36 inhibition. Circulation 151, 1234-1250 (2025).
Perdomo, G. & Henry Dong, H. Apolipoprotein D in lipid metabolism and its functional implication in atherosclerosis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1791, 827-833 (2009).
Nagae, M. et al. 3D structure and function of glycosyltransferases involved in N-glycan maturation. Int. J. Mol. Sci. 21, 437 (2020).
Miller, J. D. et al. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J. Am. Coll. Cardiol. 52, 843-850 (2008).
Hotamisligil, G. S. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47, 406-420 (2017).
Taniguchi, N. & Kizuka, Y. Glycans and cancer: role of N-glycans in cancer biomarker, progression and metastasis. Adv. Cancer Res. 126, 11-51 (2015).
Dweck, M. R. et al. Calcific aortic stenosis: a disease of the valve and the myocardium. J. Am. Coll. Cardiol. 60, 1854-1863 (2012).
指标
DOI：
Submission ID：
下载次数
已发布
如何引用
下载引用
利益冲突声明
作者声明无任何需要披露的利益冲突。
Copyright
本预印本的版权持有者为作者/资助方。
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.