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From Endothelium to Lipids, Through microRNAs and PCSK9: A Fascinating Travel Across Atherosclerosis

  • D. D’Ardes
  • F. Santilli
  • M. T. Guagnano
  • M. Bucci
  • F. CipolloneEmail author
Review article
  • 68 Downloads

Abstract

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.

Keywords

Atherosclerosis Endothelium Lipids PCSK9 miRNA 

Notes

Compliance With Ethical Standards

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Research Involving Human Participants and/or Animals

Not applicable.

Informed Consent

Not applicable.

References

  1. 1.
    Gimbrone MA. Vascular endothelium, hemodynamic forces, and atherogenesis. Am J Pathol. 1999;155:1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Partridge J, Carlsen H, Enesa K, Chaudhury H, Zakkar M, Luong L, Kinderlerer A, Johns M, Blomhoff R, Mason JC, Haskard DO, Evans PC. Laminar shear stress acts as a switch to regulate divergent functions of NF-kappaB in endothelial cells. FASEB J. 2007;21:3553–61.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Cipollone F, Rocca B, Patrono C. Cyclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol. 2004;24:246–55. PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-β is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994;370:460–2.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002;417:750–4.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Anderson TJ, Meredith IT, Charbonneau F, et al. Endothelium-dependent coronary vasomotion relates to the susceptibility to oxidation in humans. Circulation. 1996;93:1647–50.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Davì G, Santilli F. Platelets, oxidative stress and preservation of the vascular endothelium: is it a matter of fat? Intern Emerg Med. 2012;7(3):199–201.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Violi F, Sanguigni V, Carnevale R, Plebani A, Rossi P, Finocchi A, Pignata C, De Mattia D, Martire B, Pietrogrande MC, Martino S, Gambineri E, Soresina AR, Pignatelli P, Martino F, Basili S, Loffredo L. Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation. 2009;120:1616–22.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Davì G, Guagnano MT, Ciabattoni G, Basili S, Falco A, Marinopiccoli M, Nutini M, Sensi S, Patrono C. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA. 2002;288:2008–14.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Ramji DP, Davies TS. Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Fact Rev. 2015;26(6):673–85.CrossRefGoogle Scholar
  11. 11.
    Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Gieseg SP, Amit Z, Yang YT, Shchepetkina A, Katouah H. Oxidant production, oxLDL uptake, and CD36 levels in human monocyte-derived macrophages are downregulated by the macrophage-generated antioxidant 7,8-dihydroneopterin. Antioxid Redox Signal. 2010;13:1525–34.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ellison S, Gabunia K, Kelemen SE, England RN, Scalia R, Richards JM, Orr AW, Traylor JG Jr, Rogers T, Cornwell W, Berglund LM, Goncalves I, Gomez MF, Autieri MV. Attenuation of experimental atherosclerosis by interleukin–19. Arterioscler Thromb Vasc Biol. 2013;33:2316–24.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Cipollone F, Chiarelli F, Davì G, Ferri C, Desideri G, Fazia M, Iezzi A, Santilli F, Pini B, Cuccurullo C, Tumini S, Del Ponte A, Santucci A, Cuccurullo F, Mezzetti A. Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia. 2005;48(6):1216–24.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Civelek M, Manduchi E, Riley RJ, Stoeckert CJ Jr, Davies PF. Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ Res. 2009;105:453–61.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Scull CM, Tabas I. Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31:2792–7.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zeng L, Zampetaki A, Margariti A, Pepe AE, Alam S, Martin D, Xiao Q, Wang W, Jin ZG, Cockerill G, Mori K, Li YS, Hu Y, Chien S, Xu Q. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc Natl Acad Sci USA. 2009;106:8326–31.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Doddaballapur A, Michalik KM, Manavski Y, Lucas T, Houtkooper RH, You X, Chen W, Zeiher AM, Potente M, Dimmeler S, Boon RA. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol. 2015;35:137–45.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Yang Q, Li X, Li R, Peng J, Wang Z, Jiang Z, Tang X, Peng Z, Wang Y, Wei D. Low shear stress inhibited endothelial cell Autophagy through TET2 downregulation. Ann Biomed Eng. 2016;44(7):2218–27.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Takabe W, Jen N, Ai L, Hamilton R, Wang S, Holmes K, Dharbandi F, Khalsa B, Bressler S, Barr ML, Li R, Hsiai TK. Oscillatory shear stress induces mitochondrial superoxide production: implication of NADPH oxidase and c-Jun NH2-terminal kinase signaling. Antioxid Redox Signal. 2011;15:1379–88.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J Am Heart Assoc. 2017;6(12):e006910.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Zhang DW, Lagace TA, Garuti R, Zhao Z, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282:8602–18612.Google Scholar
  23. 23.
    Costet P, Krempf M, Cariou B. PCSK9 and LDL cholesterol: unravelling the target to design the bullet. Trends Biochem Sci. 2008;33:426–34.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hess CN, Low Wang CC, Hiatt WR. PCSK9 inhibitors: mechanisms of action, metabolic effects, and clinical outcomes. Annu Rev Med. 2018;69:133–45.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Demers A, Samami S, Lauzier B, Des Rosiers C, et al. PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler Thromb Vasc Biol. 2015;35:2517–25.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Canuel M, Sun X, Asselin MC, Paramithiotis E, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS One. 2013;8:e64145.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shapiro MD, Fazio S. PCSK9 and atherosclerosis—lipids and beyond. J Atheroscler Thromb. 2017;24:462–72.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ferri N, Tibolla G, Pirillo A, Cipollone F, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220:381–6.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ricci C, Ruscica M, Camera M, Rossetti L, et al. PCSK9 induces a pro-inflammatory response in macrophages. Sci Rep. 2018;8(1):2267.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ferri N, Marchiano S, Tibolla G, Baetta R, et al. PCSK9 knock-out mice are protected from neointimal formation in response to perivascular carotid collar placement. Atherosclerosis. 2016;253:214–24.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Maulucci G, Cipriani F, Russo D, Casavecchia G, et al. Improved endothelial function after short-term therapy with evolocumab. J Clin Lipidol. 2018;12:669–73.PubMedCrossRefGoogle Scholar
  32. 32.
    Cicero AFG, Toth PP, Fogacci F, Virdis A, et al. Improvement in arterial stiffness after short-term treatment with PCSK9 inhibitors. Nutr Metab Cardiovasc Dis. 2019;29:527–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Berger JM, Vaillant N, Le May C, Calderon C, et al. PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension. Atherosclerosis. 2015;239:252–9.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Yang SH, Du Y, Li S, Zhang Y. Plasma PCSK9 level is unrelated to blood pressure and not associated independently with carotid intima-media thickness in hypertensives. Hypertens Res. 2016;39:598–605.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Zufeng D, Shijie L, Xianwei W, Xiaoyan D, et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res. 2015;107(4):556–67.CrossRefGoogle Scholar
  36. 36.
    Ding Z, Liu S, Wang X, Theus S, Deng X, Fan Y, Zhou S, Mehta JL. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc Res. 2018;114(8):1145–53.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Santovito D, Mezzetti A, Cipollone F. MicroRNAs and atherosclerosis: new actors for an old movie. Nutr Metab Cardiovasc Dis. 2012;22(11):937–43.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Condorelli G, Latronico MVG, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol. 2014;63:2177–87.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefGoogle Scholar
  40. 40.
    Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–25.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Suarez Y, Wang C, Manes TD, Pober JS. Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. J Immunol. 2010;184:21–5.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Wu W, Xiao H, Laguna-Fernandez A, Villarreal G Jr, Wang KC, Geary GG, Zhang Y, Wang WC, Huang HD, Zhou J, Li YS, Chien S, Garcia-Cardena G, Shyy JY. Flow-dependent regulation of kruppel-like factor 2 is mediated by MicroRNA-92a. Circulation. 2011;124:633–41.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Potteaux S, Vion AC, Guerin CL, Boulkroun S, Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res. 2014;114:434–43.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34:2206–16.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Fang Y, Davies PF. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol. 2012;32(4):979–87.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci USA. 2008;105:1516–21.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006;108:3068–71.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Virtue A, Johnson C, Lopez-Pastraña J, Shao Y, Fu H, Li X, Li YF, Yin Y, Mai J, Rizzo V, Tordoff M, Bagi Z, Shan H, Jiang X, Wang H, Yang XF. MicroRNA-155 deficiency leads to decreased atherosclerosis, increased white adipose tissue obesity, and non-alcoholic fatty liver disease: a novel mouse model of obesity paradox. J Biol Chem. 2017;292(4):1267–87.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Fang Y, Shi C, Manduchi E, Civelek M, Davies PF. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci USA. 2010;107(30):13450–5.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Vickers KC, Landstreet SR, Levin MG, Shoucri BM, Toth CL, Taylor RC, Palmisano BT, Tabet F, Cui HL, Rye KA, Sethupathy P, Remaley AT. MicroRNA-223 coordinates cholesterol homeostasis. Proc Natl Acad Sci USA. 2014;111:14518–23.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Vickers KC, Shoucri BM, Levin MG, Wu H, Pearson DS, Osei-Hwedieh D, Collins FS, Remaley AT, Sethupathy P. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology. 2013;57:533–42.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Goedeke L, Rotllan N, Canfran-Duque A, Aranda JF, Ramirez CM, Araldi E, Lin CS, Anderson NN, Wagschal A, de Cabo R, Horton JD, Lasuncion MA, Naar AM, Suarez Y, Fernandez-Hernando C. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015;21:1280–9.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, Naar AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–9.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Ramirez CM, Davalos A, Goedeke L, Salerno AG, Warrier N, Cirera-Salinas D, Suarez Y, Fernandez-Hernando C. MicroRNA-758 regulates cholesterol efflux through posttranscriptional repression of ATP-binding cassette transporter A1. Arterioscler Thromb Vasc Biol. 2011;31:2707–14.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Sun D, Zhang J, Xie J, Wei W, Chen M, Zhao X. MiR-26 controls LXR-dependent cholesterol efflux by targeting ABCA1 and ARL7. FEBS Lett. 2012;586:1472–9.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Kim J, Yoon H, Ramirez CM, Lee SM, Hoe HS, Fernandez-Hernando C, Kim J. MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression. Exp Neurol. 2012;235:476–83.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Ramirez CM, Rotllan N, Vlassov AV, Davalos A, Li M, Goedeke L, Aranda JF, Cirera-Salinas D, Araldi E, Salerno A, Wanschel AC, Zavadil J, Castrillo A, Jungsu K, Suarez Y, Fernandez-Hernando C. Control of cholesterol metabolism and plasma HDL levels by miRNA-144. Circ Res. 2013;112:1592–601.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE −/− mice. J Am Heart Assoc. 2012;1:e003376.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Mandolini C, Santovito D, Marcantonio P, Buttitta F, Bucci M, Ucchino S, Mezzetti A, Cipollone F. Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques. Nutr Metab Cardiovasc Dis. 2015;25(2):202–9.  https://doi.org/10.1016/j.numecd.2014.09.005.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Cipollone F, Felicioni L, Sarzani R, Ucchino S, Spigonardo F, Mandolini C, Malatesta S, Bucci M, Mammarella C, Santovito D, de Lutiis F, Marchetti A, Mezzetti A, Buttitta F. A unique microRNA signature associated with plaque instability in humans. Stroke. 2011;42(9):2556–63.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Santovito D, Mandolini C, Marcantonio P, De Nardis V, Bucci M, Paganelli C, Magnacca F, Ucchino S, Mastroiacovo D, Desideri G, Mezzetti A, Cipollone F. Overexpression of microRNA-145 in atherosclerotic plaques from hypertensive patients. Expert Opin Ther Targets. 2013;17(3):217–23.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Shirahama R, Ono T, Nagamatsu S, Sueta D, Takashio S, et al. Coronary artery plaque regression by a PCSK9 antibody and rosuvastatin in double-heterozygous familial hypercholesterolemia with an LDL receptor mutation and a PCSk9 V4I mutation. Intern Med. 2018;57:3551–7.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Kumar S, Williams D, Sur S, Wang JY, Jo H. Role of flow-sensitive microRNAs and long noncoding RNAs in vascular dysfunction and atherosclerosis. Vascul Pharmacol. 2019;114:76–92.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Xu S, Xu Y, Liu P, Zhang S, Liu H, Slavin S, Kumar S, Koroleva M, Luo J, Wu X, Rahman A, Pelisek J, Jo H, Si S, Miller CL, Jin ZG. The novel coronary artery disease risk gene JCAD/KIAA1462 promotes endothelial dysfunction and atherosclerosis. Eur Heart J. 2019;40:2398–408.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Italian Society of Hypertension 2020

Authors and Affiliations

  1. 1.Department of Medicine and Aging“G. d’Annunzio” UniversityChietiItaly
  2. 2.Clinica Medica Division and European Center of Excellence on AtherosclerosisHypertension and Dyslipidemia “SS. Annunziata” HospitalChietiItaly

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