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Role of DNA damage in the pathogenesis of atherosclerosis

Published:September 12, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.08.010

      Highlights

      • Accumulating evidence indicates that genomic instability triggers inflammation.
      • Cellular senescence is involved in the mechanisms of inflammation through senescence-associated secretory phenotype.
      • Not only the microbial DNA but also the fragmented self-DNA in the cytosol can trigger inflammation.
      • Recognition of fragmented DNA in the cytosol by DNA sensors induces intracellular processes that lead to inflammation.

      Abstract

      Atherosclerosis is a cause of coronary artery disease, abdominal aortic aneurysm, and stroke. The pathogenesis underlying atherosclerosis is complex but it is clear that inflammation plays a pivotal role. Inflammation in atherosclerosis is triggered by the recognition of intracellular contents released from damaged cells by pattern recognition receptors, and is therefore sterile and chronic. Because the DNA of these cells is damaged, cellular senescence is also involved in this inflammation. Here, we will discuss the emerging evidence of a relationship between DNA damage and inflammation in the pathogenesis of atherosclerosis, with a focus on intracellular events and cell fates that arise following DNA damage. Recent evidence will lead us to potential therapeutic targets and allow us to explore potential preventative and therapeutic strategies.

      Graphical abstract

      Keywords

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      References

        • Ross R.
        • Glomset J.
        • Harker L.
        Response to injury and atherogenesis.
        Am J Pathol. 1977; 86: 675-684
        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Ishida M.
        • Ishida T.
        • Tashiro S.
        • Uchida H.
        • Sakai C.
        • Hironobe N.
        • et al.
        Smoking cessation reverses DNA double-strand breaks in human mononuclear cells.
        PLoS One. 2014; 9e103993
        • Minamino T.
        • Komuro I.
        Vascular cell senescence: contribution to atherosclerosis.
        Circ Res. 2007; 100: 15-26
        • Gudmundsrud R.
        • Skjånes T.H.
        • Gilmour B.C.
        • Caponio D.
        • Lautrup S.
        • Fang E.F.
        Crosstalk among DNA damage, mitochondrial dysfunction, impaired mitophagy, stem cell attrition, and senescence in the accelerated ageing disorder Werner syndrome.
        Cytogenet Genome Res. 2021; 161: 297-304
        • Ragu S.
        • Matos-Rodrigues G.
        • Lopez B.S.
        Replication stress, DNA damage, inflammatory cytokines and innate immune response.
        Genes. 2020; 11: 409
        • Birch J.
        • Gil J.
        Senescence and the SASP: many therapeutic avenues.
        Genes Dev. 2020; 34: 1565-1576
        • Lau E.S.
        • Paniagua S.M.
        • Liu E.
        • Jovani M.
        • Li S.X.
        • Takvorian K.
        • et al.
        Cardiovascular risk factors are associated with future cancer.
        JACC CardioOncol. 2021; 3: 48-58
        • Ishida T.
        • Ishida M.
        • Tashiro S.
        • Takeishi Y.
        DNA damage and senescence-associated inflammation in cardiovascular disease.
        Biol. Pharm. Bull. 2019; 42: 531-537
        • Zhou B.-B.S.
        • Elledge S.J.
        The DNA damage response: putting checkpoints in perspective.
        Nature. 2000; 408: 433-439
        • Shimizu I.
        • Yoshida Y.
        • Suda M.
        • Minamino T.
        DNA damage response and metabolic disease.
        Cell Metab. 2014; 20: 967-977
        • Li T.
        • Chen Z.J.
        The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer.
        Journal of Experimental Medicine. 2018; 215: 1287-1299
        • Ablasser A.
        • Hur S.
        Regulation of cGAS- and RLR-mediated immunity to nucleic acids.
        Nat Immunol. 2020; 21: 17-29
        • Miyamoto S.
        Nuclear initiated NF-κB signaling: NEMO and ATM take center stage.
        Cell Res. 2011; 21: 116-130
        • Mercer J.R.
        • Cheng K.K.
        • Figg N.
        • Gorenne I.
        • Mahmoudi M.
        • Griffin J.
        • et al.
        DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome.
        Circ Res. 2010; 107: 1021-1031
        • Eaton J.S.
        • Lin Z.P.
        • Sartorelli A.C.
        • Bonawitz N.D.
        • Shadel G.S.
        Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis.
        J Clin Invest. 2007; 117: 2723-2734
        • Lee J.H.
        • Paull T.T.
        Mitochondria at the crossroads of ATM-mediated stress signaling and regulation of reactive oxygen species.
        Redox Biol. 2020; 32101511
        • Takahashi A.
        • Loo T.M.
        • Okada R.
        • Kamachi F.
        • Watanabe Y.
        • Wakita M.
        • et al.
        Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells.
        Nat Commun. 2018; 9: 1249
        • Lan Y.Y.
        • Londoño D.
        • Bouley R.
        • Rooney M.S.
        • Hacohen N.
        Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy.
        Cell Rep. 2014; 9: 180-192
        • Ho S.S.
        • Zhang W.Y.
        • Tan N.Y.
        • Khatoo M.
        • Suter M.A.
        • Tripathi S.
        • et al.
        The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells.
        Immunity. 2016; 44: 1177-1189
        • Kumari P.
        • Russo A.J.
        • Shivcharan S.
        • Rathinam V.A.
        AIM2 in health and disease: inflammasome and beyond.
        Immunol. Rev. 2020; 297: 83-95
        • Gasser S.
        • Zhang W.Y.L.
        • Tan N.Y.J.
        • Tripathi S.
        • Suter M.A.
        • Chew Z.H.
        • et al.
        Sensing of dangerous DNA.
        Mech Ageing Dev. 2017; 165: 33-46
        • Amadio R.
        • Piperno G.M.
        • Benvenuti F.
        Self-DNA sensing by cGAS-STING and TLR9 in autoimmunity: is the cytoskeleton in control?.
        Front Immunol. 2021; 12657344
        • Fitzgerald K.A.
        • Kagan J.C.
        Toll-like receptors and the control of immunity.
        Cell. 2020; 180: 1044-1066
        • Fukuda D.
        • Nishimoto S.
        • Aini K.
        • Tanaka A.
        • Nishiguchi T.
        • Kim-Kaneyama J.R.
        • et al.
        Toll-like receptor 9 plays a pivotal role in angiotensin II-induced atherosclerosis.
        J Am Heart Assoc. 2019; 8e010860
        • Ma C.
        • Ouyang Q.
        • Huang Z.
        • Chen X.
        • Lin Y.
        • Hu W.
        • et al.
        Toll-like receptor 9 inactivation alleviated atherosclerotic progression and inhibited macrophage polarized to M1 phenotype in ApoE-/- mice.
        Dis Markers. 2015; 2015909572
        • Krogmann A.O.
        • Lüsebrink E.
        • Steinmetz M.
        • Asdonk T.
        • Lahrmann C.
        • Lütjohann D.
        • et al.
        Proinflammatory stimulation of toll-like receptor 9 with high dose CpG ODN 1826 impairs endothelial regeneration and promotes atherosclerosis in mice.
        PLoS ONE. 2016; 11e0146326
        • Koulis C.
        • Chen Y.-C.
        • Hausding C.
        • Ahrens I.
        • Kyaw T.S.
        • Tay C.
        • et al.
        Protective role for toll-like Receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice.
        Arterioscler Thromb Vasc Biol. 2014; 34: 516-525
        • Waibler Z.
        • Anzaghe M.
        • Konur A.
        • Akira S.
        • Müller W.
        • Kalinke U.
        Excessive CpG 1668 stimulation triggers IL-10 production by cDC that inhibits IFN-alpha responses by pDC.
        Eur J Immunol. 2008; 38: 3127-3137
        • Shapouri-Moghaddam A.
        • Mohammadian S.
        • Vazini H.
        • Taghadosi M.
        • Esmaeili S.A.
        • Mardani F.
        • et al.
        Macrophage plasticity, polarization, and function in health and disease.
        J Cell Physiol. 2018; 233: 6425-6440
        • Guerrier T.
        • Pochard P.
        • Lahiri A.
        • Youinou P.
        • Pers J.O.
        • Jamin C.
        TLR9 expressed on plasma membrane acts as a negative regulator of human B cell response.
        J Autoimmun. 2014; 51: 23-29
        • Barton G.M.
        • Kagan J.C.
        • Medzhitov R.
        Intracellular localization of toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA.
        Nat Immunol. 2006; 7: 49-56
        • Hong Z.
        • Ma T.
        • Liu X.
        • Wang C.
        cGAS-STING pathway: post-translational modifications and functions in sterile inflammatory diseases.
        FEBS J. 2021; https://doi.org/10.1111/febs.16137
        • Mackenzie K.J.
        • Carroll P.
        • Martin C.A.
        • Murina O.
        • Fluteau A.
        • Simpson D.J.
        • et al.
        cGAS surveillance of micronuclei links genome instability to innate immunity.
        Nature. 2017; 548: 461-465
        • Yang H.
        • Wang H.
        • Ren J.
        • Chen Q.
        • Chen Z.J.
        cGAS is essential for cellular senescence.
        Proc Natl Acad Sci U S A. 2017; 114: E4612-e20
        • Hopfner K.P.
        • Hornung V.
        Molecular mechanisms and cellular functions of cGAS-STING signalling.
        Nat Rev Mol Cell Biol. 2020; 21: 501-521
        • Kerur N.
        • Fukuda S.
        • Banerjee D.
        • Kim Y.
        • Fu D.
        • Apicella I.
        • et al.
        cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
        Nat Med. 2018; 24: 50-61
        • Gaidt M.M.
        • Ebert T.S.
        • Chauhan D.
        • Ramshorn K.
        • Pinci F.
        • Zuber S.
        • et al.
        The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3.
        Cell. 2017; 171 (e18): 1110-1124
        • Liu H.
        • Zhang H.
        • Wu X.
        • Ma D.
        • Wu J.
        • Wang L.
        • et al.
        Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.
        Nature. 2018; 563: 131-136
        • Gentili M.
        • Lahaye X.
        • Nadalin F.
        • GPF Nader
        • Puig Lombardi E.
        • Herve S.
        • et al.
        The N-terminal domain of cGASdetermines preferential association with centromeric DNA and innate immune activation in the nucleus.
        Cell Rep. 2019; 26 (e13): 2377-2393
        • Luo W.
        • Wang Y.
        • Zhang L.
        • Ren P.
        • Zhang C.
        • Li Y.
        • et al.
        Critical role of cytosolic DNA and its sensing adaptor STING in aortic degeneration, dissection, and rupture.
        Circulation. 2020; 141: 42-66
        • Pham P.T.
        • Fukuda D.
        • Nishimoto S.
        • Kim-Kaneyama J.R.
        • Lei X.F.
        • Takahashi Y.
        • et al.
        STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.
        Eur Heart J. 2021; 42: 4336-4348
        • de Vasconcelos N.M.
        • Van Opdenbosch N.
        • Lamkanfi M.
        Inflammasomes as polyvalent cell death platforms.
        Cell Mol Life Sci. 2016; 73: 2335-2347
        • Karasawa T.
        • Takahashi M.
        Role of NLRP3 inflammasomes in atherosclerosis.
        J Atheroscler Thromb. 2017; 24: 443-451
        • Pan J.
        • Han L.
        • Guo J.
        • Wang X.
        • Liu D.
        • Tian J.
        • et al.
        AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/- mice.
        Biochem Biophys Res Commun. 2018; 498: 487-494
        • Paulin N.
        • Viola J.R.
        • Maas S.L.
        • de Jong R.
        • Fernandes-Alnemri T.
        • Weber C.
        • et al.
        Double-Strand DNA sensing Aim2 inflammasome regulates atherosclerotic plaque vulnerability.
        Circulation. 2018; 138: 321-323
        • Minamino T.
        • Komuro I.
        Role of telomeres in vascular senescence.
        Front. Biosci. 2008; 13: 2971-2979
        • Rodier F.
        • Coppé J.P.
        • Patil C.K.
        • Hoeijmakers W.A.
        • Muñoz D.P.
        • Raza S.R.
        • et al.
        Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.
        Nat Cell Biol. 2009; 11: 973-979
        • Hernandez-Segura A.
        • Nehme J.
        • Demaria M.
        Hallmarks of cellular senescence.
        Trends Cell Biol. 2018; 28: 436-453
        • Glück S.
        • Guey B.
        • Gulen M.F.
        • Wolter K.
        • Kang T.W.
        • Schmacke N.A.
        • et al.
        Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.
        Nat Cell Biol. 2017; 19: 1061-1070
        • Minamino T.
        • Miyauchi H.
        • Yoshida T.
        • Ishida Y.
        • Yoshida H.
        • Komuro I.
        Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.
        Circulation. 2002; 105: 1541-1544
        • Sweeney M.
        • Cook S.A.
        • Gil J.
        Therapeutic opportunities for senolysis in cardiovascular disease.
        FEBS J. 2022; https://doi.org/10.1111/febs.16351
        • Kunieda T.
        • Minamino T.
        • Nishi J.
        • Tateno K.
        • Oyama T.
        • Katsuno T.
        • et al.
        Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway.
        Circulation. 2006; 114: 953-960
        • Baker D.J.
        • Wijshake T.
        • Tchkonia T.
        • LeBrasseur N.K.
        • Childs B.G.
        • van de Sluis B.
        • et al.
        Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
        Nature. 2011; 479: 232-236
        • Zhang L.
        • Pitcher L.E.
        • Prahalad V.
        • Niedernhofer L.J.
        • Robbins P.D.
        Targeting cellular senescence with senotherapeutics: senolytics and senomorphics.
        FEBS J. 2022; https://doi.org/10.1111/febs.16350
        • Suda M.
        • Shimizu I.
        • Katsuumi G.
        • Yoshida Y.
        • Hayashi Y.
        • Ikegami R.
        • et al.
        Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice.
        Nat Aging. 2021; 1: 1117-1126
        • Takahashi M.
        Cell-specific roles of NLRP3 inflammasome in myocardial infarction.
        J Cardiovasc Pharmacol. 2019; 74: 188-193
        • Lama L.
        • Adura C.
        • Xie W.
        • Tomita D.
        • Kamei T.
        • Kuryavyi V.
        • et al.
        Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.
        Nat Commun. 2019; 10: 2261
        • Liu K.
        • Lan Y.
        • Li X.
        • Li M.
        • Cui L.
        • Luo H.
        • et al.
        Development of small molecule inhibitors/agonists targeting STING for disease.
        Biomed Pharmacother. 2020; 132110945