Annexin A8 deficiency delays atherosclerosis progression

Carmen Gutiérrez-Muñoz , Rafael Blázquez-Serra , Irene San Sebastián-Jaraba , Sandra Sanz-Andrea , Maria J. Fernández-Gómez , Gonzalo Nuñez-Moreno , Pablo Mínguez , Joan Carles Escolá-Gil , Paula Nogales , Veronique Ollivier , Jose L. Martín-Ventura , Benoit Ho-Tin-Noe , Ursula Rescher , Nerea Méndez-Barbero , Luis M. Blanco-Colio

Clinical and Translational Medicine ›› 2025, Vol. 15 ›› Issue (1) : e70176

PDF
Clinical and Translational Medicine ›› 2025, Vol. 15 ›› Issue (1) : e70176 DOI: 10.1002/ctm2.70176
RESEARCH ARTICLE

Annexin A8 deficiency delays atherosclerosis progression

Author information +
History +
PDF

Abstract

•This study shows that AnxA8 is upregulated in aorta of atheroprone mice and in human atherosclerotic plaques.

•Germline AnxA8 deficiency reduces platelet and leukocyte recruitment to activated endothelium as well as atherosclerotic burden, plaque size, and macrophage accumulation in mice.

•AnxA8 regulates oxLDL-induced adhesion molecules expression in aortic endothelial cells. Our data strongly suggest that AnxA8 promotes disease progression through regulation of adhesion and influx of immune cells to the intima.

•Endothelial specific silencing of AnxA8 reduced atherosclerosis progression.

•Therapeutic interventions to reduce AnxA8 expression may delay atherosclerosis progression.

Keywords

AnxA8 / atherosclerosis / inflammation

Cite this article

Download citation ▾
Carmen Gutiérrez-Muñoz, Rafael Blázquez-Serra, Irene San Sebastián-Jaraba, Sandra Sanz-Andrea, Maria J. Fernández-Gómez, Gonzalo Nuñez-Moreno, Pablo Mínguez, Joan Carles Escolá-Gil, Paula Nogales, Veronique Ollivier, Jose L. Martín-Ventura, Benoit Ho-Tin-Noe, Ursula Rescher, Nerea Méndez-Barbero, Luis M. Blanco-Colio. Annexin A8 deficiency delays atherosclerosis progression. Clinical and Translational Medicine, 2025, 15(1): e70176 DOI:10.1002/ctm2.70176

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

WHO CVD Risk Chart Working Group. World Health Organization Cardiovascular Disease Risk Charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332-e1345.

[2]

Lu H, Daugherty A. Atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35(3):485-491.

[3]

Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primer. 2019;5(1):56.

[4]

Gencer S, Evans BR, van der Vorst EPC, Döring Y, Weber C. Inflammatory chemokines in atherosclerosis. Cells. 2021;10(2):226.

[5]

Sreeramkumar V, Adrover JM, Ballesteros I, et al. Neutrophils scan for activated platelets to initiate inflammation. Science. 2014;346(6214):1234-1238.

[6]

Döring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res. 2017;120(4):736-743.

[7]

Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-1866.

[8]

Schloer S, Pajonczyk D, Rescher U. Annexins in translational research: hidden treasures to be found. Int J Mol Sci. 2018;19(6):E1781.

[9]

Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev. 2002;82(2):331-371.

[10]

Grewal T, Rentero C, Enrich C, Wahba M, Raabe CA, Rescher U. Annexin animal models-from fundamental principles to translational research. Int J Mol Sci. 2021;22(7):3439.

[11]

Méndez-Barbero N, Gutiérrez-Muñoz C, Blázquez-Serra R, Martín-Ventura JL, Blanco-Colio LM. Annexins: involvement in cholesterol homeostasis, inflammatory response and atherosclerosis. Clin Investig Arterioscler. 2021;33(4):206-216.

[12]

Drechsler M, de Jong R, Rossaint J, et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ Res. 2015;116(5):827-835.

[13]

Burgmaier M, Schutters K, Willems B, et al. AnxA5 reduces plaque inflammation of advanced atherosclerotic lesions in apoE(-/-) mice. J Cell Mol Med. 2014;18(10):2117-2124.

[14]

Li H, Huang S, Wang S, et al. Targeting annexin A7 by a small molecule suppressed the activity of phosphatidylcholine-specific phospholipase C in vascular endothelial cells and inhibited atherosclerosis in apolipoprotein E/mice. Cell Death Dis. 2013;4:e806.

[15]

Poeter M, Brandherm I, Rossaint J, et al. Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63. Nat Commun. 2014;5:3738.

[16]

Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605-D612.

[17]

Morris JH, Apeltsin L, Newman AM, et al. clusterMaker: a multi-algorithm clustering plugin for Cytoscape. BMC Bioinformatics. 2011;12:436.

[18]

Mi H, Ebert D, Muruganujan A, et al. PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API. Nucleic Acids Res. 2021;49(D1):D394-D403.

[19]

Seimon TA, Wang Y, Han S, et al. Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. J Clin Invest. 2009;119(4):886-898.

[20]

Steffensen LB, Mortensen MB, Kjolby M, Hagensen MK, Oxvig C, Bentzon JF. Disturbed laminar blood flow vastly augments lipoprotein retention in the artery wall: a key mechanism distinguishing susceptible from resistant sites. Arterioscler Thromb Vasc Biol. 2015;35(9):1928-1935.

[21]

Méndez-Barbero N, Gutierrez-Muñoz C, Madrigal-Matute J, et al. A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. EBioMedicine. 2019;46:274-289.

[22]

Frenette PS, Johnson RC, Hynes RO, Wagner DD. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci U S A. 1995;92(16):7450-7454.

[23]

Gutiérrez-Muñoz C, Méndez-Barbero N, Svendsen P, et al. CD163 deficiency increases foam cell formation and plaque progression in atherosclerotic mice. FASEB J. 2020;34(11):14960-14976.

[24]

Mendez-Barbero N, Yuste-Montalvo A, Nuñez-Borque E, et al. The TNF-like weak inducer of the apoptosis/fibroblast growth factor-inducible molecule 14 axis mediates histamine and platelet-activating factor-induced subcutaneous vascular leakage and anaphylactic shock. J Allergy Clin Immunol. 2020;145(2):583-596.e6.

[25]

Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(Supp l8):C13-18.

[26]

Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341-355.

[27]

Kunjathoor VV, Febbraio M, Podrez EA, et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002;277(51):49982-49988.

[28]

Wang X, Collins HL, Ranalletta M, et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117(8):2216-2224.

[29]

Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1995;15(9):1512-1531.

[30]

Massberg S, Brand K, Grüner S, et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002;196(7):887-896.

[31]

Mauersberger C, Hinterdobler J, Schunkert H, Kessler T, Sager HB. Where the action is-leukocyte recruitment in atherosclerosis. Front Cardiovasc Med. 2021;8:813984.

[32]

Ghoshal P, Rajendran M, Odo N, Ikuta T. Glycosylation inhibitors efficiently inhibit P-selectin-mediated cell adhesion to endothelial cells. PloS One. 2014;9(6):e99363.

[33]

Yang H, Li X, Liu Y, et al. Crocin improves the endothelial function regulated by Kca3.1 through ERK and Akt signaling pathways. Cell Physiol Biochem. 2018;46(2):765-780.

[34]

Lipinski DM, Reid CA, Boye SL, et al. Systemic vascular transduction by capsid mutant adeno-associated virus after intravenous injection. Hum Gene Ther. 2015;26(11):767-776.

[35]

Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001;104(4):503-516.

[36]

Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387-401.

[37]

Shao Y, Yang WY, Saaoud F, et al. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms. JCI Insight. 2021;6(19):e152511.

[38]

Wierer M, Prestel M, Schiller HB, et al. Compartment-resolved proteomic analysis of mouse aorta during atherosclerotic plaque formation reveals osteoclast-specific protein expression. Mol Cell Proteomics. 2018;17(2):321-334.

[39]

Seita J, Sahoo D, Rossi DJ, et al. Gene Expression Commons: an open platform for absolute gene expression profiling. PLoS One. 2012;7(7):e40321.

[40]

Swirski FK, Libby P, Aikawa E, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117(1):195-205.

[41]

Itabe H. Oxidative modification of LDL: its pathological role in atherosclerosis. Clin Rev Allergy Immunol. 2009;37(1):4-11.

[42]

Wu X, Zheng X, Cheng J, Zhang K, Ma C. LncRNA TUG1 regulates proliferation and apoptosis by regulating miR-148b/IGF2 axis in ox-LDL-stimulated VSMC and HUVEC. Life Sci. 2020;243:117287.

[43]

Yuan JB, Gu L, Chen L, Yin Y, Fan BY. Annexin A8 regulated by lncRNA-TUG1/miR-140-3p axis promotes bladder cancer progression and metastasis. Mol Ther Oncolytics. 2021;22:36-51.

[44]

Tailor A, Granger DN. Hypercholesterolemia promotes P-selectin-dependent platelet-endothelial cell adhesion in postcapillary venules. Arterioscler Thromb Vasc Biol. 2003;23(4):675-680.

[45]

Lievens D, von Hundelshausen P. Platelets in atherosclerosis. Thromb Haemost. 2011;106(5):827-838.

[46]

Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115(12):3378-3384.

[47]

Valentijn KM, Sadler JE, Valentijn JA, Voorberg J, Eikenboom J. Functional architecture of Weibel−Palade bodies. Blood. 2011;117(19):5033-5043.

[48]

Yago T, Shao B, Miner JJ, et al. E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin alphaLbeta2-mediated slow leukocyte rolling. Blood. 2010;116(3):485-494.

[49]

Zarbock A, Ley K, McEver RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood. 2011;118(26):6743-6751.

[50]

Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 2000;191(1):189-194.

[51]

Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P-and E-selectins in atherosclerosis. J Clin Invest. 1998;102(1):145-152.

[52]

Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(11):2292-2301.

[53]

Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity. 2014;41(5):694-707.

[54]

Hashimoto K, Kataoka N, Nakamura E, Tsujioka K, Kajiya F. Oxidized LDL specifically promotes the initiation of monocyte invasion during transendothelial migration with upregulated PECAM-1 and downregulated VE-cadherin on endothelial junctions. Atherosclerosis. 2007;194(2):e9-17.

[55]

Harry BL, Sanders JM, Feaver RE, et al. Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2008;28(11):2003-2008.

[56]

Muller WA. Getting leukocytes to the site of inflammation. Vet Pathol. 2013;50(1):7-22.

[57]

Mamdouh Z, Chen X, Pierini LM, Maxfield FR, Muller WA. Targeted recycling of PECAM from endothelial surface-connected compartments during diapedesis. Nature. 2003;421(6924):748-753.

[58]

Jiang X, Xue S, Kang T, et al. Annexin A8 (ANXA8) regulates proliferation of porcine endometrial cells via Akt signalling pathway. Reprod Domest Anim Zuchthyg. 2019;54(1):3-10.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

AI Summary AI Mindmap
PDF

102

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/