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Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development

  • Yidong Wang
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Liangliang Jia
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Yao Xie
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Zhejun Cai
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Zhenjie Liu
    Affiliations
    Department of Vascular Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China
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  • Jian Shen
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Yi Lu
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Yaping Wang
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Shengan Su
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Yuankun Ma
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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  • Meixiang Xiang
    Correspondence
    Corresponding author.
    Affiliations
    Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Lab of Cardiovascular Disease of Zhejiang Province, Hangzhou, Zhejiang, PR China
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      Highlights

      • A large mount of exosomes were present in adventitia of aneurysmal tiusses, and mainly from macrophages.
      • GW4869, an inhibitor of exosome biogenesis, significantly reduced dilation of calcium phosphate (CaPO4)-induced AAA.
      • Macrophage-derived exosomes induced MMP-2 expression in vascular smooth muscle cells by activating JNK and p38 pathways.

      Abstract

      Background and aims

      Abdominal aortic aneurysm (AAA) is characterized by infiltration of inflammatory cells, extracellular matrix (ECM) degradation, and dysfunction of vascular smooth muscle cells (VSMCs). Recent studies reported that exosomes mediate intercellular communication and are involved in different diseases. Whether exosomes play a role in AAA is poorly understood. Hence, this study evaluated the function of exosomes in AAA development.

      Methods

      The presence of exosomes in human and calcium phosphate (CaPO4)-induced AAA tissues was determined by immunofluorescence staining of CD63 and Alix. GW4869, an inhibitor of exosome biogenesis, was intraperitoneally injected into CaPO4-induced AAA tissues to evaluate the effects of exosomal inhibition on AAA development. To explore the underlying mechanisms, the human monocytic cell line THP-1 was differentiated into macrophages, and exosomes were collected from macrophages. VSMCs were treated with macrophage-derived exosomes, and the expression of matrix metalloproteinase-2 (MMP-2) was evaluated. The activation of mitogen-activated protein kinases (MAPKs) pathways was also investigated in vitro and in vivo.

      Results

      Exosomes were detected in the adventitia of aneurysmal tissues obtained from humans and mice. They were mainly expressed in clusters of macrophages. Intraperitoneal injection of GW4869 for two weeks significantly attenuated the progression of CaPO4-induced AAA, preserved elastin integrity and decreased MMP-2 expression. Similarly, administration of GW4869 suppressed the systemic and aneurysmal exosome generation. In vitro, treatment with macrophage-derived exosomes elevated MMP-2 expression in human VSMCs, while pre-treatment with GW4869 abolished these effects. It was also found that JNK and p38 pathways mediated the production of MMP-2 in VSMCs following treatment with macrophage-derived exosomes.

      Conclusions

      This study suggests that exosomes derived from macrophages are involved in the pathogenesis of AAA. Macrophage-derived exosomes trigger MMP-2 expression in VSMC via JNK and p38 pathways. GW4869 supplementation attenuates CaPO4-induced AAA in mice.

      Graphical abstract

      Keywords

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      References

        • Wang Y.D.
        • Liu Z.J.
        • Ren J.
        • Xiang M.X.
        Pharmacological therapy of abdominal aortic aneurysm: an update.
        Curr. Vasc. Pharmacol. 2018; 16: 114-124
        • Riches K.
        • Clark E.
        • Helliwell R.J.
        • Angelini T.G.
        • Hemmings K.E.
        • et al.
        Progressive development of aberrant smooth muscle cell phenotype in abdominal aortic aneurysm disease.
        J. Vasc. Res. 2018; 55: 35-46
        • Raffort J.
        • Lareyre F.
        • Clément M.
        • Hassen-Khodja R.
        • Chinetti G.
        • Mallat Z.
        Monocytes and macrophages in abdominal aortic aneurysm.
        Nat. Rev. Cardiol. 2017; 14: 457-471
        • Longo G.M.
        • Xiong W.
        • Greiner T.C.
        • Zhao Y.
        • Fiotti N.
        • Baxter B.T.
        Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms.
        J.Clin.Invest. 2002; 110: 625-632
        • Ghosh A.
        • Pechota L.V.
        • Upchurch Jr., G.R.
        • Eliason J.L.
        Cross-talk between macrophages, smooth muscle cells, and endothelial cells in response to cigarette smoke: the effects on MMP2 and 9.
        Mol. Cell. Biochem. 2015; 410: 75-84
        • Butoi E.
        • Gan A.M.
        • Tucureanu M.M.
        • Stan D.
        • Macarie R.D.
        • et al.
        Cross-talk between macrophages and smooth muscle cells impairs collagen and metalloprotease synthesis and promotes angiogenesis.
        Biochim. Biophys. Acta. 2016; 1863: 1568-1578
        • Ibrahim A.
        • Marban E.
        Exosomes: fundamental biology and roles in cardiovascular physiology.
        Annu. Rev. Physiol. 2016; 78: 67-83
        • Boulanger C.M.
        • Loyer X.
        • Rautou P.E.
        • Amabile N.
        Extracellular vesicles in coronary artery disease.
        Nat. Rev. Cardiol. 2017; 14: 259-272
        • Zhang C.
        • Zhang K.
        • Huang F.
        • Feng W.
        • Chen J.
        • Zhang H.
        • Wang J.
        • Luo P.
        • Huang H.
        Exosomes, the message transporters in vascular calcification.
        J. Cell Mol. Med. 2018; 22: 4024-4033
        • Essandoh K.
        • Yang L.
        • Wang X.
        • Huang W.
        • Qin D.
        • et al.
        Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.
        Biochim. Biophys. Acta. 2015; 1852: 2362-2371
        • Dinkins M.B.
        • Dasgupta S.
        • Wang G.
        • Zhu G.
        • Bieberich E.
        Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease.
        Neurobiol. Aging. 2014; 35: 1792-1800
        • Ismail N.
        • Wang Y.
        • Dakhlallah D.
        • Moldovan L.
        • Agarwal K.
        • et al.
        Macrophage microvesicles induce macrophage differentiation and miR-223 transfer.
        Blood. 2013; 121: 984-995
        • Niu C.
        • Wang X.
        • Zhao M.
        • Cai T.
        • Liu P.
        • et al.
        Macrophage foam cell-derived extracellular vesicles promote vascular smooth muscle cell migration and adhesion.
        J. Am.Heart.Assoc. 2016; 5e004099
        • Osada-Oka M.
        • Shiota M.
        • Izumi Y.
        • Nishiyama M.
        • Tanaka M.
        • et al.
        Macrophage-derived exosomes induce inflammatory factors in endothelial cells under hypertensive conditions.
        Hypertens. Res. 2016; 40: 353-360
        • Spinosa M.
        • Lu G.
        • Su G.
        • Bontha S.V.
        • Gehrau R.
        • et al.
        Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147.
        FASEB (Fed. Am. Soc. Exp. Biol.) J. 2018; (fj201701138RR)https://doi.org/10.1096/fj.201701138RR
        • Yamanouchi D.
        • Morgan S.
        • Stair C.
        • Seedial S.
        • Lengfeld J.
        • et al.
        Accelerated aneurysmal dilation associated with apoptosis and inflammation in a newly developed calcium phosphate rodent abdominal aortic aneurysm model.
        J. Vasc. Surg. 2012; 56: 455-461
        • Liu Z.
        • Morgan S.
        • Ren J.
        • Wang Q.
        • Annis D.S.
        • et al.
        Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm.
        Circ. Res. 2015; 117: 129-141
        • Morgan S.
        • Yamanouchi D.
        • Harberg C.
        • Wang Q.
        • Keller M.
        • et al.
        Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.
        Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2493-2502
        • Holder B.
        • Jones T.
        • Sancho Shimizu V.
        • Rice T.F.
        • Donaldson B.
        • et al.
        Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging.
        Traffic. 2016; 17: 168-178
        • Kapustin A.N.
        • Chatrou M.L.
        • Drozdov I.
        • Zheng Y.
        • Davidson S.M.
        • et al.
        Vascular smooth muscle cell calcification is mediated by regulated exosome secretion.
        Circ. Res. 2015; 116: 1312-1323
        • Cho A A.
        • Graves J.
        • Reidy M.A.
        Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells, Arterioscler.
        Thromb.Vasc.Biol. 2000; 20: 2527-2532
        • Park H.S.
        • Quan K.T.
        • Han J.H.
        • Jung S.H.
        • Lee D.H.
        • et al.
        Rubiarbonone C inhibits platelet-derived growth factor-induced proliferation and migration of vascular smooth muscle cells through the focal adhesion kinase, MAPK and STAT3 Tyr705 signaling pathways.
        Br. J. Pharmacol. 2017; 174: 4140-4154
        • Chistiakov D.A.
        • Orekhov A.N.
        • Bobryshev Y.V.
        Extracellular vesicles and atherosclerotic disease.
        Cell. Mol. Life Sci. 2015; 72: 2697-2708
        • Tang N.
        • Sun B.
        • Gupta A.
        • Rempel H.
        • Pulliam L.
        Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-kappaB in endothelial cells.
        FASEB (Fed. Am. Soc. Exp. Biol.) J. 2016; 30: 3097-3106
        • Kapustin A.N.
        • Schoppet M.
        • Schurgers L.J.
        • Reynolds J.L.
        • McNair R.
        • et al.
        Prothrombin loading of vascular smooth muscle cell-derived exosomes regulates coagulation and calcification.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: e22-e32
        • Asai H.
        • Ikezu S.
        • Tsunoda S.
        • Medalla M.
        • Luebke J.
        • et al.
        Depletion of microglia and inhibition of exosome synthesis halt tau propagation.
        Nat. Neurosci. 2015; 18: 1584-1593
        • Lallemand T.
        • Rouahi M.
        • Swiader A.
        • Grazide M.H.
        • Geoffre N.
        • et al.
        nSMase2 (Type 2-Neutral Sphingomyelinase) deficiency or inhibition by GW4869 reduces inflammation and atherosclerosis in Apoe-/- mice.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: 1479-1492
        • Zhong L.
        • He X.
        • Si X.
        • Wang H.
        • Li B.
        • et al.
        SM22α(Smooth Muscle 22α) prevents aortic aneurysm formation by inhibiting smooth muscle cell phenotypic switching through suppressing reactive oxygen species/NF-κB (Nuclear Factor-κB).
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: e10-e25
        • Yang X.X.
        • Sun C.
        • Wang L.
        • Guo X.L.
        New insight into isolation, identification techniques and medical applications of exosomes.
        J. Control. Release. 2019; 17: 119-129