РОЛЬ КЛЕТОЧНОЙ ПЛАСТИЧНОСТИ КЛЕТОК СОСУДИСТОЙ СТЕНКИ И КРОВЕТВОРНОЙ СИСТЕМЫ В АТЕРОГЕНЕЗЕ

Основные положения

• Атеросклеротический процесс обусловлен фенотипической гетерогенностью и пластичностью клеток иммунной системы и сосудистой стенки.
• Соматические мутации и клональный гемопоэз с неопределенным потенциалом демонстрируют тесную связь с сердечно-сосудистыми заболеваниями и острыми сосудистыми событиями.

Резюме

Прогресс, достигнутый за последнее десятилетие в области кардиогенетики, ознаменован главным образом работами, основанными на оценке наследуемых герминативных мутаций. Новые направления продемонстрировали значительную роль клеточной пластичности, соматического мозаицизма и клонального гемопоэза в структуре риска развития ишемической болезни сердца, а также острых сосудистых нарушений атерогенного происхождения. Секвенирование единичных клеток и масс-цитометрия позволили раскрыть принципиально новые механизмы развития атеросклероза. В обзоре освещены современные данные в области изучения атеросклероза и сосудистых нарушений с фокусом на клеточную пластичность, соматический мозаицизм и клональный гемопоэз.

1. Herrington W., Lacey B., Sherliker P., Armitage J., Lewington S. Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circ Res. 2016;118:535–546. doi: 10.1161/CIRCRESAHA.115.307611.

2. Ridker P.M., MacFadyen J.G., Everett B.M., Libby P., Thuren T., Glynn R.J. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391:319–328. doi: 10.1016/S0140-6736(17)32814-3.

3. Tang D.G. Understanding cancer stem cell heterogeneity and plasticity. Cell Res. 2012;22:457–472. doi: 10.1038/cr.2012.13.

4. Jaiswal S., Ebert B.L. Clonal hematopoiesis in human aging and disease. Science. 2019;366(6465). doi:10.1126/science.aan4673

5. Laurie C.C., Laurie C.A., Rice K., Doheny K.F., Zelnick L.R., McHugh C.P., Ling H., Hetrick K.N., et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44:642–650. doi: 10.1038/ng.2271.

6. Bick A.G., Weinstock J.S., Nandakumar S.K., Fulco C.P., Bao E.L., Zekavat S.M., Szeto M.D., Liao X., et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature. 2020;586:763–768. doi: 10.1038/s41586-020-2819-2.

7. Jaiswal S., Natarajan P., Silver A.J., Gibson C.J., Bick A.G., Shvartz E., McConkey M., Gupta N., Gabriel S., Ardissino D., Baber U., Mehran R., Fuster V., Danesh J., Frossard P., Saleheen D., Melander O., Sukhova G.K., Neuberg D., Libby P., Kathiresan S., Ebert B.L. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017;377:111–121. doi: 10.1056/NEJMoa1701719.

8. Zhang X., Sessa W.C., Fernández-Hernando C. Endothelial Transcytosis of Lipoproteins in Atherosclerosis. Front Cardiovasc Med. 2018;5:130. doi: 10.3389/fcvm.2018.00130.

9. Borén J., Williams K.J. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol. 2016;27:473–483. doi: 10.1097/MOL.0000000000000330.

10. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592:524–533. doi: 10.1038/s41586-021-03392-8.

11. Ahmad F., Mitchell R.D., Houben T., Palo A., Yadati T., Parnell A.J., Patel K., Shiri-Sverdlov R., Leake D.S. Cysteamine Decreases Low-Density Lipoprotein Oxidation, Causes Regression of Atherosclerosis, and Improves Liver and Muscle Function in Low-Density Lipoprotein Receptor-Deficient Mice. J Am Heart Assoc. 2021;10:e017524. doi: 10.1161/JAHA.120.017524.

12. Gimbrone M.A.J., García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016;118:620–636. doi: 10.1161/CIRCRESAHA.115.306301.

13. Doran A.C., Meller N., McNamara C.A. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:812–819. doi: 10.1161/ATVBAHA.107.159327.

14. Hao H., Gabbiani G., Bochaton-Piallat M.L. Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis development. Arterioscler Thromb Vasc Biol. 2003;23:1510–1520. doi: 10.1161/01.ATV.0000090130.85752.ED.

15. Allahverdian S., Chaabane C., Boukais K., Francis G.A., Bochaton-Piallat M.L. Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovasc Res. 2018;114:540–550. doi: 10.1093/cvr/cvy022.

16. Aherrahrou R., Guo L., Nagraj V.P., Aguhob A., Hinkle J., Chen L., Yuhl Soh J., Lue D., et al. Genetic Regulation of Atherosclerosis-Relevant Phenotypes in Human Vascular Smooth Muscle Cells. Circ Res. 2020;127:1552–1565. doi: 10.1161/CIRCRESAHA.120.317415.

17. Basatemur G.L., Jørgensen H.F., Clarke M.C.H., Bennett M.R., Mallat Z. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 2019;16:727–744. doi: 10.1038/s41569-019-0227-9.

18. Dobnikar L., Taylor A.L., Chappell J., Oldach P., Harman J.L., Oerton E., Dzierzak E., Bennett M.R., Spivakov M., Jørgensen H.F. Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nat Commun. 2018;9:4567. doi: 10.1038/s41467-018-06891-x.

19. El Agha E., Kramann R., Schneider R.K., Li X., Seeger W., Humphreys B.D., Bellusci S. Mesenchymal Stem Cells in Fibrotic Disease. Cell Stem Cell. 2017;21:166–177. doi: 10.1016/j.stem.2017.07.011.

20. Chappell J., Harman J.L., Narasimhan V.M., Yu H., Foote K., Simons B.D., Bennett M.R., Jørgensen H.F. Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models. Circ Res. 2016;119:1313–1323. doi: 10.1161/CIRCRESAHA.116.309799.

21. Newman A.A.C., Serbulea V., Baylis R.A., Shankman L.S., Bradley X., Alencar G.F., Owsiany K., Deaton R.A., Karnewar S., Shamsuzzaman S., Salamon A., Reddy M.S., Guo L., Finn A., Virmani R., Cherepanova O.A., Owens G.K. Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms. Nat Metab. 2021;3:166–181. doi: 10.1038/s42255-020-00338-8.

22. Majesky M.W., Dong X.R., Hoglund V., Daum G., Mahoney W.M.J. The adventitia: a progenitor cell niche for the vessel wall. Cells Tissues Organs. 2012;195:73–81. doi: 10.1159/000331413.

23. Hu Y., Zhang Z., Torsney E., Afzal A.R, Davison F., Metzler B., Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest. 2004;113:1258–1265. doi: 10.1172/JCI19628.

24. Kramann R., Goettsch C., Wongboonsin J., Iwata H., Schneider R.K., Kuppe C., Kaesler N., Chang-Panesso M., Machado F.G., Gratwohl S., Madhurima K., Hutcheson J.D., Jain S., Aikawa E., Humphreys B.D. Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. Cell Stem Cell. 2016;19:628–642. doi: 10.1016/j.stem.2016.08.001.

25. Evrard S.M., Lecce L., Michelis K.C., Nomura-Kitabayashi A., Pandey G., Purushothaman K.R., d'Escamard V., Li J.R., Hadri L., Fujitani K., Moreno P.R., Benard L., Rimmele P., Cohain A., Mecham B., Randolph G.J., Nabel E.G., Hajjar R., Fuster V., Boehm M., Kovacic J.C. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun. 2016;7:11853. doi: 10.1038/ncomms11853.

26. Wilson H.M. Macrophages heterogeneity in atherosclerosis - implications for therapy. J Cell Mol Med. 2010;14:2055–2065. doi: 10.1111/j.1582-4934.2010.01121.x.

27. Nagenborg J., Goossens P., Biessen E.A.L., Donners M.M.P.C. Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment. Eur J Pharmacol. 2017;816:14–24. doi: 10.1016/j.ejphar.2017.10.005.

28. Tse K., Tse H., Sidney J., Sette A., Ley K. T cells in atherosclerosis. Int Immunol. 2013;25:615–622. doi: 10.1093/intimm/dxt043.

29. Cochain C., Vafadarnejad E., Arampatzi P., Pelisek J., Winkels H., Ley K., Wolf D., Saliba A.E., Zernecke A. Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis. Circ Res. 2018;122:1661–1674. doi: 10.1161/CIRCRESAHA.117.312509.

30. Depuydt M.A.C., Prange K.H.M., Slenders L., Örd T., Elbersen D., Boltjes A., de Jager S.C.A., Asselbergs F.W., de Borst G.J., Aavik E., Lönnberg T., Lutgens E., Glass C.K., den Ruijter H.M., Kaikkonen M.U., Bot I., Slütter B., van der Laan S.W., Yla-Herttuala S., Mokry M., Kuiper J., de Winther M.P.J., Pasterkamp G. Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics. Circ Res. 2020;127:1437–1455. doi: 10.1161/CIRCRESAHA.120.316770.

31. Fernandez D.M., Rahman A.H., Fernandez N.F., Chudnovskiy A., Amir E.D., Amadori L., Khan N.S., Wong C.K., Shamailova R., Hill C.A., Wang Z., Remark R., Li J.R., Pina C., Faries C., Awad A.J., Moss N., Bjorkegren J.L.M., Kim-Schulze S., Gnjatic S., Ma'ayan A., Mocco J., Faries P., Merad M., Giannarelli C. Single-cell immune landscape of human atherosclerotic plaques. Nat Med. 2019;25:1576–1588. doi: 10.1038/s41591-019-0590-4.

32. Abplanalp W.T., Tucker N., Dimmeler S. Single-cell technologies to decipher cardiovascular diseases. Eur Heart J. 2022. doi: 10.1093/eurheartj/ehac095.

33. Sharma M., Schlegel M.P., Afonso M.S., Brown E.J., Rahman K., Weinstock A., Sansbury B.E., Corr E.M., van Solingen C., Koelwyn G.J., Shanley L.C., Beckett L., Peled D., Lafaille J.J., Spite M., Loke P., Fisher E.A., Moore K.J. Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression. Circ Res. 2020;127:335–353. doi: 10.1161/CIRCRESAHA.119.316461.

34. Marnell C.S., Bick A., Natarajan P. Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J Mol Cell Cardiol. 2021;161:98–105. doi: 10.1016/j.yjmcc.2021.07.004.

35. Sano S., Oshima K., Wang Y., Katanasaka Y., Sano M., Walsh K. CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res. 2018;123:335–341. doi: 10.1161/CIRCRESAHA.118.313225.

36. Fuster J.J., MacLauchlan S., Zuriaga M.A., Polackal M.N., Ostriker A.C., Chakraborty R., Wu C.L., Sano S., Muralidharan S., Rius C., Vuong J., Jacob S., Muralidhar V., Robertson A.A., Cooper M.A., Andrés V., Hirschi K.K., Martin K.A., Walsh K. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–847. doi: 10.1126/science.aag1381.

37. Sano S., Oshima K., Wang Y., MacLauchlan S., Katanasaka Y., Sano M., Zuriaga M.A., Yoshiyama M., Goukassian D., Cooper M.A., Fuster J.J., Walsh K. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J Am Coll Cardiol. 2018;71:875–886. doi: 10.1016/j.jacc.2017.12.037.

38. Masamoto Y., Arai S., Sato T., Yoshimi A., Kubota N., Takamoto I., Iwakura Y., Yoshimura A., Kadowaki T., Kurokawa M. Adiponectin Enhances Antibacterial Activity of Hematopoietic Cells by Suppressing Bone Marrow Inflammation. Immunity. 2016;44:1422–1433. doi: 10.1016/j.immuni.2016.05.010.

39. Asada S., Kitamura T. Clonal hematopoiesis and associated diseases: A review of recent findings. Cancer Sci. 2021;112:3962–3971. doi: 10.1111/cas.15094.

40. Dawoud A.A.Z., Tapper W.J., Cross NCP. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia. 2020;34:2660–2672. doi: 10.1038/s41375-020-0896-8.

41. Misawa K., Yasuda H., Araki M., Ochiai T., Morishita S., Shirane S., Edahiro Y., Gotoh A., Ohsaka A., Komatsu N. Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. Int J Hematol. 2018;107:673–680. doi: 10.1007/s12185-018-2421-7.

42. Wang W., Liu W., Fidler T., Wang Y., Tang Y., Woods B., Welch C., Cai B., Silvestre-Roig C., Ai D., Yang Y.G., Hidalgo A., Soehnlein O., Tabas I., Levine R.L., Tall A.R., Wang N. Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 V617F Mice. Circ Res. 2018;123:e35–e47. doi: 10.1161/CIRCRESAHA.118.313283.

43. Papa V., Marracino L., Fortini F., Rizzo P., Campo G., Vaccarezza M., Vieceli Dalla Sega F. Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review. J Clin Med. 2020;9. doi: 10.3390/jcm9082480.

44. Hsu J.I., Dayaram T., Tovy A., De Braekeleer E., Jeong M., Wang F., Zhang J., Heffernan T.P., Gera S., Kovacs J.J., Marszalek J.R., Bristow C., Yan Y., Garcia-Manero G., Kantarjian H., Vassiliou G., Futreal P.A., Donehower L.A., Takahashi K., Goodell M.A. PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy. Cell Stem Cell. 2018;23:700–713.e6. doi: 10.1016/j.stem.2018.10.004.

45. Calvillo-Argüelles O., Jaiswal S., Shlush L.I., Moslehi J.J., Schimmer A., Barac A., Thavendiranathan P. Connections Between Clonal Hematopoiesis, Cardiovascular Disease, and Cancer: A Review. JAMA Cardiol. 2019;4:380–387. doi: 10.1001/jamacardio.2019.0302.

46. Zink F., Stacey S.N., Norddahl G.L., Frigge M.L., Magnusson O.T., Jonsdottir I., Thorgeirsson T.E., Sigurdsson A., Gudjonsson S.A., Gudmundsson J., Jonasson J.G., Tryggvadottir L., Jonsson T., Helgason A., Gylfason A., Sulem P., Rafnar T., Thorsteinsdottir U., Gudbjartsson D.F., Masson G., Kong A., Stefansson K. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130:742–752. doi: 10.1182/blood-2017-02-769869.

47. Nazarenko M.S., Sleptcov A.A., Lebedev I.N., Skryabin N.A., Markov A.V., Golubenko M.V., Koroleva I.A., Kazancev A.N., Barbarash O.L., Puzyrev V.P. Genomic structural variations for cardiovascular and metabolic comorbidity. Sci Rep. 2017 Jan 25;7:41268. doi: 10.1038/srep41268.

48. Bonnefond A., Skrobek B., Lobbens S., Eury E., Thuillier D., Cauchi S., Lantieri O., Balkau B., Riboli E., Marre M., Charpentier G., Yengo L., Froguel P. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat Genet. 2013;45:1040–1043. doi: 10.1038/ng.2700.