Skip to content
2000
image of EFHD1: A Potential Prognostic Biomarker Related to Mitochondrial Function and Aging in Atherosclerosis Plaque
file format pdf download PDF

Abstract

Introduction

Atherosclerosis (AS) is prevalent among the elderly population and poses a significant global health burden. However, the precise underlying mechanisms linking aging and mitochondrial dysfunction in AS remain unclear.

Methods

Through comprehensive utilization of databases including the Gene Expression Omnibus (GEO), MitoCarta, Molecular Signatures Database (MSigDB), and Human Aging Genomic Resources (HAGR), we employed various bioinformatics methods to explore the possible function of EF-hand domain family member D1 (EFHD1). This included the functional enrichment analysis, immune cell infiltration, and the lncRNA-miRNA-EFHD1 network. The validity of EFHD1 was confirmed using additional datasets and through Receiver Operating Characteristic (ROC) curve evaluation. Lastly, experiments were conducted using THP-1 cells treated with oxidized low-density lipoprotein (ox-LDL) to validate the expression and function of EFHD1 through Western blot and real-time quantitative PCR analyses. Additionally, experiments were performed on ApoE-/- mice exhibiting atherosclerotic phenotypes, utilizing immunofluorescence staining.

Results

Totally seven genes associated with aging and mitochondrial function (ALDH3A2, UCP1, BCL2, EFHD1, AHCYL1, HTRA2, and ALDH9A1) were discovered in AS, with EFHD1 identified as the principal hub gene. Immune infiltration analysis indicated that EFHD1 was negatively associated with myeloid suppressor cells (MDSC), activated B cells, and natural killer cells. An evident decline in EFHD1 was noted in unstable or advanced plaques compared to stable or early plaques, accompanied by significant area under the ROC curve (AUC) values of 0.917 (GSE100927) and 0.933 (GSE41571). Moreover, we recorded a reduction in EFHD1 expression in AS tissues and macrophages treated with ox-LDL. Following the silencing of EFHD1, TNF-α and IL-1β decreased, while ALODA, PKM2, MMP-9, JAK2, and STAT3 levels were upregulated. Furthermore, levels of ATP and reactive oxygen species (ROS) were diminished, while calcium ions and mitochondria levels remained unchanged.

Discussion

To date, the common pathogenic genes associated with aging and mitochondrial dysfunction in atherosclerotic disease have been scarcely investigated. Using bioinformatics approaches, we identified seven hub genes (ALDH3A2, UCP1, BCL2, EFHD1, AHCYL1, HTRA2, and ALDH9A1) related to mitochondrial function and aging. Among these, EFHD1 was determined as the final hub gene. As a calcium sensor, EFHD1 plays a pivotal role in regulating mitochondrial metabolism and has been implicated in the prognosis of various tumors. Our findings demonstrated that EFHD1 knockdown decreased the levels of pro-inflammatory cytokines, such as IL-1β and TNF-α, increased JAK2 and STAT3 protein levels, and elevated MMP-9 levels, all of which may contribute to the vulnerability and progression of atherosclerotic plaques.

Conclusion

Our research revealed a reduction in EFHD1 expression within atherosclerotic tissues, suggesting its potential role in inflammation and mitochondrial energy metabolism as a key regulator of the calcium signaling pathway. This discovery offers possible advancements in the early diagnosis and treatment strategies for AS.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673356904250628182630
2025-07-21
2025-11-05

  • From This Site

    /content/journals/cmc/10.2174/0109298673356904250628182630
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmc/10.2174/0109298673356904250628182630/BMS-CMC-2024-684.html?itemId=/content/journals/cmc/10.2174/0109298673356904250628182630&mimeType=html&fmt=ahah

References

  1. Farhat N. Thorin-Trescases N. Voghel G. Villeneuve L. Mamarbachi M. Perrault L.P. Carrier M. Thorin E. Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. Can. J. Physiol. Pharmacol. 2008 86 11 761 769 10.1139/Y08‑082 19011671
    [Google Scholar]
  2. Niemann B. Chen Y. Teschner M. Li L. Silber R.E. Rohrbach S. Obesity induces signs of premature cardiac aging in younger patients: The role of mitochondria. J. Am. Coll. Cardiol. 2011 57 5 577 585 10.1016/j.jacc.2010.09.040 21272749
    [Google Scholar]
  3. Wang J.C. Bennett M. Aging and atherosclerosis. Circ. Res. 2012 111 2 245 259 10.1161/CIRCRESAHA.111.261388 22773427
    [Google Scholar]
  4. Wang M. Zhang J. Jiang L.Q. Spinetti G. Pintus G. Monticone R. Kolodgie F.D. Virmani R. Lakatta E.G. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 2007 50 1 219 227 10.1161/HYPERTENSIONAHA.107.089409 17452499
    [Google Scholar]
  5. Hariri R.J. Hajjar D.P. Coletti D. Alonso D.R. Weksler M.E. Rabellino E. Aging and arteriosclerosis. Cell cycle kinetics of young and old arterial smooth muscle cells. Am. J. Pathol. 1988 131 1 132 136 3354639
    [Google Scholar]
  6. Gerhard M. Roddy M.A. Creager S.J. Creager M.A. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996 27 4 849 853 10.1161/01.HYP.27.4.849 8613259
    [Google Scholar]
  7. Toupance S. Labat C. Temmar M. Rossignol P. Kimura M. Aviv A. Benetos A. Short telomeres, but not telomere attrition rates, are associated with carotid atherosclerosis. Hypertension 2017 70 2 420 425 10.1161/HYPERTENSIONAHA.117.09354 28630210
    [Google Scholar]
  8. Hu H. Cheng X. Li F. Guan Z. Xu J. Wu D. Gao Y. Zhan X. Wang P. Zhou H. Rao Z. Cheng F. Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury. Cell Death Discov. 2023 9 1 236 10.1038/s41420‑023‑01497‑9 37422464
    [Google Scholar]
  9. Yue Z. Nie L. Zhao P. Ji N. Liao G. Wang Q. Senescence-associated secretory phenotype and its impact on oral immune homeostasis. Front. Immunol. 2022 13 1019313 10.3389/fimmu.2022.1019313 36275775
    [Google Scholar]
  10. Zhao L. Lv F. Zheng Y. Yan L. Cao X. Characterization of an aging-based diagnostic gene signature and molecular subtypes with diverse immune infiltrations in atherosclerosis. Front. Mol. Biosci. 2022 8 792540 10.3389/fmolb.2021.792540 35096968
    [Google Scholar]
  11. Fu Y. Zhang J. Liu Q. Yang L. Wu Q. Yang X. Wang L. Ding N. Xiong J. Gao Y. Ma S. Jiang Y. Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression. Inflamm. Res. 2024 73 1 65 82 10.1007/s00011‑023‑01817‑w 38062164
    [Google Scholar]
  12. Ciccarelli G. Conte S. Cimmino G. Maiorano P. Morrione A. Giordano A. Mitochondrial dysfunction: The hidden player in the pathogenesis of atherosclerosis? Int. J. Mol. Sci. 2023 24 2 1086 10.3390/ijms24021086 36674602
    [Google Scholar]
  13. Wang Y. Dubland J.A. Allahverdian S. Asonye E. Sahin B. Jaw J.E. Sin D.D. Seidman M.A. Leeper N.J. Francis G.A. Smooth muscle cells contribute the majority of foam cells in apoe (apolipoprotein e)-deficient mouse atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2019 39 5 876 887 10.1161/ATVBAHA.119.312434 30786740
    [Google Scholar]
  14. Tan S.M. Sharma A. Yuen D.Y.C. Stefanovic N. Krippner G. Mugesh G. Chai Z. de Haan J.B. The modified selenenyl amide, M-hydroxy ebselen, attenuates diabetic nephropathy and diabetes-associated atherosclerosis in ApoE/GPx1 double knockout mice. PLoS One 2013 8 7 69193 10.1371/journal.pone.0069193 23874911
    [Google Scholar]
  15. Sun N. Youle R.J. Finkel T. The mitochondrial basis of aging. Mol. Cell 2016 61 5 654 666 10.1016/j.molcel.2016.01.028 26942670
    [Google Scholar]
  16. Caparosa E.M. Sedgewick A.J. Zenonos G. Zhao Y. Carlisle D.L. Stefaneanu L. Jankowitz B.T. Gardner P. Chang Y.F. Lariviere W.R. LaFramboise W.A. Benos P.V. Friedlander R.M. Regional molecular signature of the symptomatic atherosclerotic carotid plaque. Neurosurgery 2019 85 2 E284 E293 10.1093/neuros/nyy470 30335165
    [Google Scholar]
  17. Döring Y. Manthey H.D. Drechsler M. Lievens D. Megens R.T.A. Soehnlein O. Busch M. Manca M. Koenen R.R. Pelisek J. Daemen M.J. Lutgens E. Zenke M. Binder C.J. Weber C. Zernecke A. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 2012 125 13 1673 1683 10.1161/CIRCULATIONAHA.111.046755 22388324
    [Google Scholar]
  18. Wang R. Xu J. Tang Y. Wang Y. Zhao J. Ding L. Peng Y. Zhang Z. Transcriptome-wide analysis reveals the coregulation of RNA-binding proteins and alternative splicing genes in the development of atherosclerosis. Sci. Rep. 2023 13 1 1764 10.1038/s41598‑022‑26556‑6 36720950
    [Google Scholar]
  19. Steenman M. Espitia O. Maurel B. Guyomarch B. Heymann M.F. Pistorius M.A. Ory B. Heymann D. Houlgatte R. Gouëffic Y. Quillard T. Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries. Sci. Rep. 2018 8 1 3940 10.1038/s41598‑018‑22292‑y 29500419
    [Google Scholar]
  20. Lee K. Santibanez-Koref M. Polvikoski T. Birchall D. Mendelow A.D. Keavney B. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis 2013 226 1 74 81 10.1016/j.atherosclerosis.2012.09.037 23122912
    [Google Scholar]
  21. Jin H. Zhang C. Nagenborg J. Juhasz P. Ruder A.V. Sikkink C.J.J.M. Mees B.M.E. Waring O. Sluimer J.C. Neumann D. Goossens P. Donners M.M.P.C. Mardinoglu A. Biessen E.A.L. Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability. Cardiovasc. Diabetol. 2024 23 1 240 10.1186/s12933‑024‑02339‑3 38978031
    [Google Scholar]
  22. Ayari H. Bricca G. Identification of two genes potentially associated in iron-heme homeostasis in human carotid plaque using microarray analysis. J. Biosci. 2013 38 2 311 315 10.1007/s12038‑013‑9310‑2 23660665
    [Google Scholar]
  23. Mahmoud A.D. Ballantyne M.D. Miscianinov V. Pinel K. Hung J. Scanlon J.P. Iyinikkel J. Kaczynski J. Tavares A.S. Bradshaw A.C. Mills N.L. Newby D.E. Caporali A. Gould G.W. George S.J. Ulitsky I. Sluimer J.C. Rodor J. Baker A.H. The human-specific and smooth muscle cell-enriched LncRNA SMILR promotes proliferation by regulating mitotic CENPF mRNA and drives cell-cycle progression which can be targeted to limit vascular remodeling. Circ. Res. 2019 125 5 535 551 10.1161/CIRCRESAHA.119.314876 31339449
    [Google Scholar]
  24. Rath S. Sharma R. Gupta R. Ast T. Chan C. Durham T.J. Goodman R.P. Grabarek Z. Haas M.E. Hung W.H.W. Joshi P.R. Jourdain A.A. Kim S.H. Kotrys A.V. Lam S.S. McCoy J.G. Meisel J.D. Miranda M. Panda A. Patgiri A. Rogers R. Sadre S. Shah H. Skinner O.S. To T.L. Walker M.A. Wang H. Ward P.S. Wengrod J. Yuan C.C. Calvo S.E. Mootha V.K. MitoCarta3.0: An updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021 49 D1 D1541 D1547 10.1093/nar/gkaa1011 33174596
    [Google Scholar]
  25. Adelman R.C. Secretion of insulin during aging. J. Am. Geriatr. Soc. 1989 37 10 983 990 10.1111/j.1532‑5415.1989.tb07287.x 2677102
    [Google Scholar]
  26. Lv Y. Wu L. Jian H. Zhang C. Lou Y. Kang Y. Hou M. Li Z. Li X. Sun B. Zhou H. Identification and characterization of aging/senescence-induced genes in osteosarcoma and predicting clinical prognosis. Front. Immunol. 2022 13 997765 10.3389/fimmu.2022.997765 36275664
    [Google Scholar]
  27. Zhang Q. Li J. Weng L. Identification and validation of aging-related genes in Alzheimer’s disease. Front. Neurosci. 2022 16 905722 10.3389/fnins.2022.905722 35615282
    [Google Scholar]
  28. Barrett T. Wilhite S.E. Ledoux P. Evangelista C. Kim I.F. Tomashevsky M. Marshall K.A. Phillippy K.H. Sherman P.M. Holko M. Yefanov A. Lee H. Zhang N. Robertson C.L. Serova N. Davis S. Soboleva A. NCBI GEO: Archive for functional genomics data sets—update. Nucleic Acids Res. 2012 41 D1 D991 D995 10.1093/nar/gks1193 23193258
    [Google Scholar]
  29. Yi C. Liu J. Deng W. Luo C. Qi J. Chen M. Xu H. Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis. J. Neuroinflammation 2022 19 1 78 10.1186/s12974‑022‑02433‑x 35382832
    [Google Scholar]
  30. Langfelder P. Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008 9 1 559 10.1186/1471‑2105‑9‑559 19114008
    [Google Scholar]
  31. Nangraj A.S. Selvaraj G. Kaliamurthi S. Kaushik A.C. Cho W.C. Wei D.Q. Integrated PPI- and WGCNA-Retrieval of hub gene signatures shared between barrett’s esophagus and esophageal adenocarcinoma. Front. Pharmacol. 2020 11 881 10.3389/fphar.2020.00881 32903837
    [Google Scholar]
  32. Robin X. Turck N. Hainard A. Tiberti N. Lisacek F. Sanchez J.C. Müller M. pROC: An open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011 12 1 77 10.1186/1471‑2105‑12‑77 21414208
    [Google Scholar]
  33. Yu G. Wang L.G. Han Y. He Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012 16 5 284 287 10.1089/omi.2011.0118 22455463
    [Google Scholar]
  34. Chang L. Zhou G. Soufan O. Xia J. miRNet 2.0: Network-based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. 2020 48 W1 W244 W251 10.1093/nar/gkaa467 32484539
    [Google Scholar]
  35. Li J.H. Liu S. Zhou H. Qu L.H. Yang J.H. starBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014 42 D1 D92 D97 10.1093/nar/gkt1248 24297251
    [Google Scholar]
  36. Chen Y. Wang X. miRDB: An online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020 48 D1 D127 D131 10.1093/nar/gkz757 31504780
    [Google Scholar]
  37. Sticht C. De La Torre C. Parveen A. Gretz N. miRWalk: An online resource for prediction of microRNA binding sites. PLoS One 2018 13 10 0206239 10.1371/journal.pone.0206239 30335862
    [Google Scholar]
  38. Crépet A. Papadopoulos A. Elegbede C.F. Ait-Dahmane S. Loynet C. Millet G. Van Der Brempt X. Bruyère O. Marette S. Moneret-Vautrin D.A. Mirabel: An integrated project for risk and cost/benefit analysis of peanut allergy. Regul. Toxicol. Pharmacol. 2015 71 2 178 183 10.1016/j.yrtph.2014.12.006 25523940
    [Google Scholar]
  39. Kern F. Krammes L. Danz K. Diener C. Kehl T. Küchler O. Fehlmann T. Kahraman M. Rheinheimer S. Aparicio-Puerta E. Wagner S. Ludwig N. Backes C. Lenhof H.P. von Briesen H. Hart M. Keller A. Meese E. Validation of human microRNA target pathways enables evaluation of target prediction tools. Nucleic Acids Res. 2021 49 1 127 144 10.1093/nar/gkaa1161 33305319
    [Google Scholar]
  40. Davis A.P. Wiegers T.C. Johnson R.J. Sciaky D. Wiegers J. Mattingly C.J. Comparative toxicogenomics database (CTD): Update 2023. Nucleic Acids Res. 2023 51 D1 D1257 D1262 10.1093/nar/gkac833 36169237
    [Google Scholar]
  41. Shannon P. Markiel A. Ozier O. Baliga N.S. Wang J.T. Ramage D. Amin N. Schwikowski B. Ideker T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003 13 11 2498 2504 10.1101/gr.1239303 14597658
    [Google Scholar]
  42. Charoentong P. Finotello F. Angelova M. Mayer C. Efremova M. Rieder D. Hackl H. Trajanoski Z. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017 18 1 248 262 10.1016/j.celrep.2016.12.019 28052254
    [Google Scholar]
  43. Yang X. Jia J. Yu Z. Duanmu Z. He H. Chen S. Qu C. Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC Cardiovasc. Disord. 2020 20 1 133 10.1186/s12872‑020‑01391‑7 32169038
    [Google Scholar]
  44. Xie Z. Yuan Y. Shi J. Shi X. Gao X. Zhao Y. Ye J. Feng X. Metformin inhibits THP-1 macrophage-derived foam cell formation induced by lipopolysaccharide. Xibao Yu Fenzi Mianyixue Zazhi 2016 32 2 168 172 26927374
    [Google Scholar]
  45. Zhang Q. Li Z. Liu X. Zhao M. Recombinant humanized igg1 antibody protects against oxldl-induced oxidative stress and apoptosis in human monocyte/macrophage THP-1 cells by upregulation of MSRA via Sirt1-FOXO1 axis. Int. J. Mol. Sci. 2022 23 19 11718 10.3390/ijms231911718 36233020
    [Google Scholar]
  46. Feng Z. Zhou J. Liu Y. Xia R. Li Q. Yan L. Chen Q. Chen X. Jiang Y. Chao G. Wang M. Zhou G. Zhang Y. Wang Y. Xia H. Epithelium- and endothelium-derived exosomes regulate the alveolar macrophages by targeting RGS1 mediated calcium signaling-dependent immune response. Cell Death Differ. 2021 28 7 2238 2256 10.1038/s41418‑021‑00750‑x 33753901
    [Google Scholar]
  47. Hao H. Cao L. Jiang C. Che Y. Zhang S. Takahashi S. Wang G. Gonzalez F.J. Farnesoid X. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 2017 25 4 856 867.e5 10.1016/j.cmet.2017.03.007 28380377
    [Google Scholar]
  48. Chen J. Zhang P. Zhao Y. Zhao J. Wu X. Zhang R. Cha R. Yao Q. Gao Y. Nitroreductase-instructed supramolecular assemblies for microbiome regulation to enhance colorectal cancer treatments. Sci. Adv. 2022 8 45 eadd2789 10.1126/sciadv.add2789 36351016
    [Google Scholar]
  49. Sanada J. Kimura T. Shimoda M. Iwamoto Y. Iwamoto H. Dan K. Fushimi Y. Katakura Y. Nogami Y. Shirakiya Y. Yamasaki Y. Ikeda T. Nakanishi S. Mune T. Kaku K. Kaneto H. Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ. Cardiovasc. Diabetol. 2024 23 1 105 10.1186/s12933‑024‑02189‑z 38504316
    [Google Scholar]
  50. Li Y. Niu X. Xu H. Li Q. Meng L. He M. Zhang J. Zhang Z. Zhang Z. VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis. Exp. Cell Res. 2020 389 1 111847 10.1016/j.yexcr.2020.111847 31972218
    [Google Scholar]
  51. Bai X. Wang Y. Luo X. Bao X. Weng X. Chen Y. Zhang S. Lv Y. Dai X. Zeng M. Yang D. Hu S. Li J. Ji Y. Jia H. Yu B. Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells. Cell Commun. Signal. 2024 22 1 41 10.1186/s12964‑024‑01480‑6 38229167
    [Google Scholar]
  52. Yang X.Y. Yu H. Fu J. Guo H.H. Han P. Ma S.R. Pan L.B. Zhang Z.W. Xu H. Hu J.C. Zhang H.J. Bu M.M. Zhang X.F. Yang W. Wang J.Y. Jin J.Y. Zhang H.C. Li D.R. Lu J.Y. Lin Y. Jiang J.D. Tong Q. Wang Y. Hydroxyurea ameliorates atherosclerosis in ApoE -/- mice by potentially modulating Niemann-Pick C1-like 1 protein through the gut microbiota. Theranostics 2022 12 18 7775 7787 10.7150/thno.76805 36451858
    [Google Scholar]
  53. Li Y. G Zhang C. Wang X-H. Liu D-H. Progression of atherosclerosis in ApoE-knockout mice fed on a high-fat diet. Eur. Rev. Med. Pharmacol. Sci. 2016 20 18 3863 3867 27735029
    [Google Scholar]
  54. Feng X. Du M. Li S. Zhang Y. Ding J. Wang J. Wang Y. Liu P. Hydroxysafflor yellow A regulates lymphangiogenesis and inflammation via the inhibition of PI3K on regulating AKT/mTOR and NF-κB pathway in macrophages to reduce atherosclerosis in ApoE-/- mice. Phytomedicine 2023 112 154684 10.1016/j.phymed.2023.154684 36738477
    [Google Scholar]
  55. Wolf D. Ley K. Immunity and inflammation in atherosclerosis. Circ. Res. 2019 124 2 315 327 10.1161/CIRCRESAHA.118.313591 30653442
    [Google Scholar]
  56. Miwa S. Kashyap S. Chini E. von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J. Clin. Invest. 2022 132 13 158447 10.1172/JCI158447 35775483
    [Google Scholar]
  57. Safaeian L. Abed A. Vaseghi G. The role of Bcl-2 family proteins in pulmonary fibrosis. Eur. J. Pharmacol. 2014 741 281 289 10.1016/j.ejphar.2014.07.029 25058906
    [Google Scholar]
  58. Hafezi S. Rahmani M. Targeting BCL-2 in cancer: Advances, challenges, and perspectives. Cancers 2021 13 6 1292 10.3390/cancers13061292 33799470
    [Google Scholar]
  59. Rykaczewska U. Zhao Q. Saliba-Gustafsson P. Lengquist M. Kronqvist M. Bergman O. Huang Z. Lund K. Waden K. Pons Vila Z. Caidahl K. Skogsberg J. Vukojevic V. Lindeman J.H.N. Roy J. Hansson G.K. Treuter E. Leeper N.J. Eriksson P. Ehrenborg E. Razuvaev A. Hedin U. Matic L. Plaque evaluation by ultrasound and transcriptomics reveals BCLAF1 as a regulator of smooth muscle cell lipid transdifferentiation in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2022 42 5 659 676 10.1161/ATVBAHA.121.317018 35321563
    [Google Scholar]
  60. Zhao R.Z. Jiang S. Zhang L. Yu Z.B. Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int. J. Mol. Med. 2019 44 1 3 15 10.3892/ijmm.2019.4188 31115493
    [Google Scholar]
  61. Fu X. Sun Z. Long Q. Tan W. Ding H. Liu X. Wu L. Wang Y. Zhang W. Glycosides from buyang huanwu decoction inhibit atherosclerotic inflammation via JAK/STAT signaling pathway. Phytomedicine 2022 105 154385 10.1016/j.phymed.2022.154385 35987015
    [Google Scholar]
  62. Cadenas S. Mitochondrial uncoupling, ROS generation and cardioprotection. Biochim. Biophys. Acta Bioenerg. 2018 1859 9 940 950 10.1016/j.bbabio.2018.05.019 29859845
    [Google Scholar]
  63. Gu P. Hui X. Zheng Q. Gao Y. Jin L. Jiang W. Zhou C. Liu T. Huang Y. Liu Q. Nie T. Wang Y. Wang Y. Zhao J. Xu A. Mitochondrial uncoupling protein 1 antagonizes atherosclerosis by blocking NLRP3 inflammasome–dependent interleukin-1β production. Sci. Adv. 2021 7 50 eabl4024 10.1126/sciadv.abl4024 34878840
    [Google Scholar]
  64. Liu Q. Yan X. Yuan Y. Li R. Zhao Y. Fu J. Wang J. Su J. HTRA2/OMI-mediated mitochondrial quality control alters macrophage polarization affecting systemic chronic inflammation. Int. J. Mol. Sci. 2024 25 3 1577 10.3390/ijms25031577 38338855
    [Google Scholar]
  65. Xu Z. Lin J. Xie Y. Tang H. Xie J. Zeng R. HtrA2 is required for inflammatory responses in BMDMs via controlling TRAF2 stability in collagen-induced arthritis. Mol. Immunol. 2021 129 78 85 10.1016/j.molimm.2020.10.024 33229071
    [Google Scholar]
  66. Su D. Su Z. Wang J. Yang S. Ma J. UCF-101, a novel Omi/HtrA2 inhibitor, protects against cerebral ischemia/reperfusion injury in rats. Anat. Rec. 2009 292 6 854 861 10.1002/ar.20910 19462455
    [Google Scholar]
  67. Chen W. Wu X. Hu J. Liu X. Guo Z. Wu J. Shao Y. Hao M. Zhang S. Hu W. Wang Y. Zhang M. Zhu M. Wang C. Wu Y. Wang J. Xing D. The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. Cardiovasc. Diabetol. 2024 23 1 21 10.1186/s12933‑024‑02119‑z 38195542
    [Google Scholar]
  68. Mun S.A. Park J. Park K.R. Lee Y. Kang J.Y. Park T. Jin M. Yang J. Jun C.D. Eom S.H. Structural and biochemical characterization of efhd1/swiprosin-2, an actin-binding protein in mitochondria. Front. Cell Dev. Biol. 2021 8 628222 10.3389/fcell.2020.628222 33537316
    [Google Scholar]
  69. Hou T. Jian C. Xu J. Huang A.Y. Xi J. Hu K. Wei L. Cheng H. Wang X. Identification of EFHD1 as a novel Ca2+ sensor for mitoflash activation. Cell Calcium 2016 59 5 262 270 10.1016/j.ceca.2016.03.002 26975899
    [Google Scholar]
  70. Ulisse V. Dey S. Rothbard D.E. Zeevi E. Gokhman I. Dadosh T. Minis A. Yaron A. Regulation of axonal morphogenesis by the mitochondrial protein Efhd1. Life Sci. Alliance 2020 3 7 202000753 10.26508/lsa.202000753 32414840
    [Google Scholar]
  71. Zheng H. Han X. Liu Q. Zhou L. Zhu Y. Wang J. Hu W. Zhu F. Liu R. Construction of immune-related molecular diagnostic and predictive models of hepatocellular carcinoma based on machine learning. Heliyon 2024 10 2 24854 10.1016/j.heliyon.2024.e24854 38312556
    [Google Scholar]
  72. Meng K. Hu Y. Wang D. Li Y. Shi F. Lu J. Wang Y. Cao Y. Zhang C.Z. He Q.Y. EFHD1, a novel mitochondrial regulator of tumor metastasis in clear cell renal cell carcinoma. Cancer Sci. 2023 114 5 2029 2040 10.1111/cas.15749 36747492
    [Google Scholar]
  73. Takane K. Midorikawa Y. Yagi K. Sakai A. Aburatani H. Takayama T. Kaneda A. Aberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients. Cancer Med. 2014 3 5 1235 1245 10.1002/cam4.273 24861485
    [Google Scholar]
  74. Zhao B. Wang S. Xue L. Wang Q. Liu Y. Xu Q. Xue Q. EFHD1 expression is correlated with tumor-infiltrating neutrophils and predicts prognosis in gastric cancer. Heliyon 2023 9 10 21062 10.1016/j.heliyon.2023.e21062 37876466
    [Google Scholar]
  75. Grabstein K.H. Eisenman J. Shanebeck K. Rauch C. Srinivasan S. Fung V. Beers C. Richardson J. Schoenborn M.A. Ahdieh M. Johnson L. Alderson M.R. Watson J.D. Anderson D.M. Giri J.G. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 1994 264 5161 965 968 10.1126/science.8178155 8178155
    [Google Scholar]
  76. Giri J.G. Anderson D.M. Kumaki S. Park L.S. Grabstein K.H. Cosman D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J. Leukoc. Biol. 1995 57 5 763 766 10.1002/jlb.57.5.763 7759955
    [Google Scholar]
  77. Carson W. Caligiuri M.A. Interleukin-15 as a potential regulator of the innate immune response. Braz. J. Med. Biol. Res. 1998 31 1 1 9 10.1590/S0100‑879X1998000100001 9686173
    [Google Scholar]
  78. Carson W.E. Giri J.G. Lindemann M.J. Linett M.L. Ahdieh M. Paxton R. Anderson D. Eisenmann J. Grabstein K. Caligiuri M.A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med. 1994 180 4 1395 1403 10.1084/jem.180.4.1395 7523571
    [Google Scholar]
  79. Angeles-Martínez J. Posadas-Sánchez R. Pérez-Hernández N. Rodríguez-Pérez J.M. Fragoso J.M. Bravo-Flores E. Posadas-Romero C. Vargas-Alarcón G. IL-15 polymorphisms are associated with subclinical atherosclerosis and cardiovascular risk factors. The Genetics of Atherosclerosis Disease (GEA) Mexican Study. Cytokine 2017 99 173 178 10.1016/j.cyto.2017.09.006 28923712
    [Google Scholar]
  80. Wuttge D.M. Eriksson P. Sirsjö A. Hansson G.K. Stemme S. Expression of interleukin-15 in mouse and human atherosclerotic lesions. Am. J. Pathol. 2001 159 2 417 423 10.1016/S0002‑9440(10)61712‑9 11485899
    [Google Scholar]
  81. Houtkamp M.A. van der Wal A.C. de Boer O.J. van der Loos C.M. de Boer P.A.J. Moorman A.F.M. Becker A.E. Interleukin-15 expression in atherosclerotic plaques: An alternative pathway for T-cell activation in atherosclerosis? Arterioscler. Thromb. Vasc. Biol. 2001 21 7 1208 1213 10.1161/hq0701.092162 11451753
    [Google Scholar]
  82. Stein M. Dütting S. Mougiakakos D. Bösl M. Fritsch K. Reimer D. Urbanczyk S. Steinmetz T. Schuh W. Bozec A. Winkler T.H. Jäck H.M. Mielenz D. A defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1. Cell Death Differ. 2017 24 7 1239 1252 10.1038/cdd.2017.52 28524857
    [Google Scholar]
  83. Eberhardt D.R. Lee S.H. Yin X. Balynas A.M. Rekate E.C. Kraiss J.N. Lang M.J. Walsh M.A. Streiff M.E. Corbin A.C. Li Y. Funai K. Sachse F.B. Chaudhuri D. EFHD1 ablation inhibits cardiac mitoflash activation and protects cardiomyocytes from ischemia. J. Mol. Cell. Cardiol. 2022 167 1 14 10.1016/j.yjmcc.2022.03.002 35304170
    [Google Scholar]
  84. Baldini C. Moriconi F.R. Galimberti S. Libby P. De Caterina R. The JAK–STAT pathway: An emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur. Heart J. 2021 42 42 4389 4400 10.1093/eurheartj/ehab447 34343257
    [Google Scholar]
  85. Hou P. Fang J. Liu Z. Shi Y. Agostini M. Bernassola F. Bove P. Candi E. Rovella V. Sica G. Sun Q. Wang Y. Scimeca M. Federici M. Mauriello A. Melino G. Macrophage polarization and metabolism in atherosclerosis. Cell Death Dis. 2023 14 10 691 10.1038/s41419‑023‑06206‑z 37863894
    [Google Scholar]
  86. Vats D. Mukundan L. Odegaard J.I. Zhang L. Smith K.L. Morel C.R. Greaves D.R. Murray P.J. Chawla A. Chawla A. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab. 2006 4 1 13 24 10.1016/j.cmet.2006.05.011 16814729
    [Google Scholar]
  87. Mills E.L. Kelly B. Logan A. Costa A.S.H. Varma M. Bryant C.E. Tourlomousis P. Däbritz J.H.M. Gottlieb E. Latorre I. Corr S.C. McManus G. Ryan D. Jacobs H.T. Szibor M. Xavier R.J. Braun T. Frezza C. Murphy M.P. O’Neill L.A. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016 167 2 457 470.e13 10.1016/j.cell.2016.08.064 27667687
    [Google Scholar]
  88. Aluganti Narasimhulu C. Burge K.Y. Doomra M. Riad A. Parthasarathy S. Primary prevention of atherosclerosis by pretreatment of low-density lipoprotein receptor knockout mice with sesame oil and its aqueous components. Sci. Rep. 2018 8 1 12270 10.1038/s41598‑018‑29849‑x 30115989
    [Google Scholar]
  89. He Z. Wang Y. He Q. Chen M. microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9. Open Med. 2020 15 1 492 500 10.1515/med‑2020‑0047 33313408
    [Google Scholar]
  90. Shi Z. Zheng Z. Lin X. Ma H. Long Noncoding R.N.A. Long noncoding RNA MALAT1 regulates the progression of atherosclerosis by miR-330-5p/NF-κB signal pathway. J. Cardiovasc. Pharmacol. 2021 78 2 235 246 10.1097/FJC.0000000000001061 34554676
    [Google Scholar]
  91. Cremer S. Michalik K.M. Fischer A. Pfisterer L. Jaé N. Winter C. Boon R.A. Muhly-Reinholz M. John D. Uchida S. Weber C. Poller W. Günther S. Braun T. Li D.Y. Maegdefessel L. Perisic Matic L. Hedin U. Soehnlein O. Zeiher A. Dimmeler S. Hematopoietic deficiency of the long noncoding RNA MALAT1 promotes atherosclerosis and plaque inflammation. Circulation 2019 139 10 1320 1334 10.1161/CIRCULATIONAHA.117.029015 30586743
    [Google Scholar]
  92. Yang K. Xue Y. Gao X. LncRNA XIST promotes atherosclerosis by regulating miR-599/TLR4 axis. Inflammation 2021 44 3 965 973 10.1007/s10753‑020‑01391‑x 33566259
    [Google Scholar]
  93. Zhao J. Cui L. Sun J. Xie Z. Zhang L. Ding Z. Quan X. Notoginsenoside R1 alleviates oxidized low-density lipoprotein-induced apoptosis, inflammatory response, and oxidative stress in HUVECS through modulation of XIST/miR-221-3p/TRAF6 axis. Cell. Signal. 2020 76 109781 10.1016/j.cellsig.2020.109781 32947021
    [Google Scholar]
  94. Wang Y. Yang Y. Zhang T. Jia S. Ma X. Zhang M. Wang L. Ma A. LncRNA SNHG16 accelerates atherosclerosis and promotes ox-LDL-induced VSMC growth via the miRNA-22–3p/HMGB2 axis. Eur. J. Pharmacol. 2022 915 174601 10.1016/j.ejphar.2021.174601 34699756
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673356904250628182630
Loading
EFHD1: A Potential Prognostic Biomarker Related to Mitochondrial Function and Aging in Atherosclerosis Plaque
Bentham Science Publishers ; https://doi.org/10.2174/0109298673356904250628182630
/content/journals/cmc/10.2174/0109298673356904250628182630
/content/journals/cmc/10.2174/0109298673356904250628182630
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: Atherosclerosis ; aging ; mitochondrial dysfunction ; calcium signaling pathway ; GEO ; EFHD1

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test