Статья
Периваскулярная жировая ткань и атеросклероз: фенотипические особенности и терапевтический потенциал
Настоящий обзор посвящен анализу данных по изучению эндокринной функции периваскулярной жировой ткани (ПВЖТ), ее роли в синтезе и секреции гормонов адипоцитов – адипокинов (лептина, адипонектина, резистина). Отражены результаты исследований о возможных системных и локальных эффектах ПВЖТ. Продемонстрированы данные о фенотипической принадлежности ПВЖТ, особенностях ее эндокринной и паракринной функций. Про- и противовоспалительные агенты, выделяемые ПВЖТ, влияют на васкулярное здоровье и вовлечены в патогенетические механизмы развития атеросклероза. Обобщены современные данные о том, что ПВЖТ относится к особым типам жировой ткани с точки зрения как функциональности, происхождения, так и роли в развитии сердечно-сосудистых заболеваний, провоцируемых ожирением. В целом ПВЖТ может рассматриваться в качестве перспективной фармакологической мишени для профилактики сердечно-сосудистых рисков, связанных с этими заболеваниями.
1. Afshin A., Forouzanfar M.H., Reitsma M.B. et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 2017; 377: 13–27. doi: 10.1056/NEJMoa1614362
2. Chen Y., Pan R., Pfeifer A. Fat tissues, the brite and the dark sides. Pflugers Arch. 2016; 468: 1803–1807. doi: 10.1007/s00424-016-1884-8
3. Hildebrand S., Stümer J., Pfeifer A. PVAT and Its Relation to Brown, Beige, and White Adipose Tissue in Development and Function. Front. Physiol. 2018; 9: 70. doi: 10.3389/fphys.2018.00070
4. Britton K.A., Fox C.S. Perivascular adipose tissue and vascular disease. Clin. Lipidol. 2011; 6: 79–91. doi: 10.2217/clp.10.89
5. Бородкина Д.А., Груздева О.В., Квиткова Л. В., Барбараш О.Л. Можно ли назвать висцеральное ожирение ключевым фактором парадокса ожирения? Пробл. эндокринологии. 2017; 62 (6): 33–39. doi: 10.14341/probl201662633-39
6. Chen Y., Pan R., Pfeifer A. Regulation of brown and beige fat by microRNAs. Pharmacol. Ther. 2017; 170: 1–7. doi:10.1016/j.pharmthera.2016.10.004
7. Duncan R.E., Ahmadian M., Jaworski K., SarkadiNagy E., Sul H.S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 2007; 27: 79–101. doi: 10.1146/annurev.nutr.27.061406.093734
8. Hudak C.S., Sul H.S. Pref-1, a gatekeeper of adipogenesis. Front. Endocrinol. 2013; 4: 79. doi: 10.3389/fendo.2013.00079
9. Wang W., Kissig M., Rajakumari S., Huang L., Lim H., Won K.-J., Seale P. Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc. Natl. Acad. Sci. USA. 2014; 111: 14466–14471. doi: 10.1073/pnas.1412685111
10. Hong K.Y., Bae H., Park I., Park D.-Y., Kim K.H., Kubota Y., Cho E.-S., Kim H., Adams R.H., Yoo O.-J., Koh G.Y. Perilipin+ embryonic preadipocytes actively proliferate along growing vasculatures for adipose expansion. Development. 2015; 142: 2623–2632. doi: 10.1242/dev.125336
11. Pfeifer A., Hoffmann L.S. Brown, beige, and white: the new color code of fat and its pharmacological implications. Annu. Rev. Pharmacol. Toxicol. 2015; 55: 207–227. doi: 10.1146/annurev-pharmtox-010814-124346
12. Gnad T., Scheibler S., von Kügelgen I. Scheele C., Kilić A., Glöde A., Hoffmann L.S., Reverte-Salisa L., Horn P., Mutlu S., El-Tayeb A., Kranz M., DeutherConrad W., Brust P., Lidell M.E., Betz M.J., Enerbäck S., Schrader J., Yegutkin G.G., Müller C.E., Pfeifer A. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature. 2014; 516: 395–399. doi: 10.1038/nature13816
13. Tseng Y.H., Kokkotou E., Schulz T.J., Huang T.L., Winnay J.N., Taniguchi C.M., Tran T.T., Suzuki R., Espinoza D.O., Yamamoto Y., Ahrens M.J., Dudley A.T., Norris A.W., Kulkarni R.N., Kahn C. R. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008; 454: 1000–1004. doi: 10.1038/nature07221
14. Hondares E., Rosell M., Diaz-Delfin J. Olmos Y., Monsalve M., Iglesias R., Villarroya F., Giralt M. Peroxisome proliferator-activated receptor alpha (PPAR alpha) induces PPAR gamma coactivator 1 alpha (PGC-1 alpha) gene expression and contributes to thermogenic activation of brown fat involvement of PRDM16. J. Biol. Chem. 2011; 286: 43112–43122. doi: 10.1074/jbc.M111.252775
15. Cohen P., Levy J.D., Zhang Y., Frontini A., Kolodin D.P., Svensson K.J., Lo J.C., Zeng X., Ye L., Khandekar M.J., Wu J., Gunawardana S.C., Banks A.S., Camporez J.P., Jurczak M.J., Kajimura S., Piston D.W., Mathis D., Cinti S., Shulman G.I., Seale P., Spiegelman B.M. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell. 2014; 156: 304–316. doi: 10.1016/j.cell.2013.12.021
16. van Marken Lichtenbelt W.D., Vanhommerig J.W., Smulders N.M., Drossaerts J.M.A.F.L., Kemerink G.J., Bouvy N.D., Schrauwen P., Teule G.J. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 2009; 360: 1500–1508. doi: 10.1056/NEJMoa0808718
17. Shimizu I., Aprahamian T., Kikuchi R., Shimizu A., Papanicolaou K.N., MacLauchlan S., Maruyama S., Walsh K. Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. 2014; 124: 2099– 2112. doi: 10.1172/JCI71643
18. Xue B., Rim J.S., Hogan J.C., Coulter A.A, Koza R.A., Kozak L.P. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 2007; 48: 41–51. doi: 10.1194/jlr.M600287-JLR200
19. Lo K.A., Sun L. Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci. Rep. 2013; 33: 711–719. doi: 10.1042/BSR20130046
20. Harms M., Seale P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 2013; 19: 1252–1263. doi: 10.1038/nm.3361
21. Seale P., Bjork B., Yang W.L., Kajimura S., Chin S., Kuang S., Scimé A., Devarakonda S., Conroe H.M., Erdjument-Bromage H., Tempst P., Rudnicki M.A., Beier D.R., Spiegelman B.M.. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008; 454: 961–967. doi: 10.1038/nature07182
22. Rosenwald M., Perdikari A., Rülicke T., Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 2013; 15: 659–667. doi: 10.1038/ncb2740
23. Gálvez-Prieto B., Bolbrinker J., Stucchi P., de Las Heras A.I., Merino B., Arribas S., Ruiz-Gayo M., Huber M., Wehland M., Kreutz R., Fernandez-Alfonso M.S. Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue. J. Endocrinol. 2008; 197: 55–64. doi: 10.1677/JOE-07-0284
24. Police S.B., Thatcher S.E., Charnigo R., Daugherty A., Cassis L.A. Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1458–1464. doi: 10.1161/ATVBAHA.109.192658
25. Fitzgibbons T.P., Czech M.P. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J. Am. Heart Assoc. 2014; 3:e000582. doi: 10.1161/JAHA.113.000582
26. Omar A., Chatterjee T.K., Tang Y.L., Hui D.Y., Weintraub N.L. Proinflammatory phenotype of perivascular adipocytes. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 1631–1636. doi: 10.1161/ATVBAHA.114.303030
27. Chang L., Villacorta L., Li R., Hamblin M., Xu W., Dou C., Zhang J., Wu J., Zeng R., Chen Y.E. Loss of perivascular adipose tissue on peroxisome proliferatoractivated receptor-gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation. 2012; 126: 1067– 1078. doi: 10.1161/CIRCULATIONAHA.112.104489
28. Li H., Wang Y.P., Zhang L.N., Tian G. Perivascular adipose tissue-derived leptin promotes vascular smooth muscle cell phenotypic switching via p38 mitogen-activated protein kinase in metabolic syndrome rats. Exp. Biol. Med. 2014; 239: 954–965. doi: 10.1177/1535370214527903
29. Sanchez-Gurmaches J., Hung C.M., Sparks C.A., Tang Y., Li H., Guertin D.A. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab. 2012; 16: 348–362. doi: 10.1016/j.cmet.2012.08.003
30. Eringa E.C., Bakker W., van Hinsbergh V.W. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Vasc. Pharmacol. 2012; 56: 204–209. doi: 10.1016/j.vph.2012.02.003
31. Chatterjee T.K., Stoll L.L., Denning G.M., Harrelson A., Blomkalns A.L., Idelman G., Rothenberg F.G., Neltner B., Romig-Martin S.A., Dickson E.W., Rudich S., Weintraub N.L. Proinflammatory phenotype of perivascular adipocytes: Influence of high-fat feeding. Circ. Res. 2009; 104: 541–549. doi: 10.1161/circresaha.108.182998
32. Bulloch J.M., Daly C.J. Autonomic nerves and perivascular fat: Interactive mechanisms. Pharmacol. Ther. 2014; 143: 61–73. doi: 10.1016/j.pharmthera.2014.02.005
33. Ross R., Glomset J.A. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science. 1973; 180: 1332–1339. doi: 10.1126/science.180.4093.1332
34. van Dam A.D., Boon M.R., Berbée J.F., Rensen P.C., van Harmelen V. Targeting white, brown and perivascular adipose tissue in atherosclerosis development. Eur. J. Pharmacol. 2017; 816: 82–92. doi: 10.1016/j.ejphar.2017.03.051
35. Beltowski J., Wojcicka G., Marciniak A., Jamroz A. Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension. Life Sci. 2004; 74: 2987–3000. doi: 10.1016/j.lfs.2003.10.029
36. Dick G.M., Katz P.S., Farias M., Morris M.I., James J., Knudson J.D., Tune J.D. Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. Am. J. Physiol. Heart. Circ. Physiol. 2006; 291: H2997–H3002. doi: 10.1152/ajpheart.01035.2005
37. Zhang H., Park Y., Wu J., Chen X., Lee S., Yang J., Dellsperger K.C., Zhang C. Role of TNF-alpha in vascular dysfunction. Clin. Sci. (Lond). 2009; 116: 219–230. doi: 10.1042/cs20080196
38. Beltowski J., Jamroz-Wisniewska A., Widomska S. Adiponectin and its role in cardiovascular diseases. Cardiovasc. Hematol. Disord. Drug Targets. 2008; 8: 7–46. doi: 10.2174/187152908783884920
39. Greif M., Becker A., von Ziegler F., Lebherz C., Lehrke M., Broedl U.C., Tittus J., Parhofer K., Becker C., Reiser M., Knez A., Leber A.W. Pericardial adipose tissue determined by dual source CT is a risk factor for coronary atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 781–786. doi: 10.1161/atvbaha.108.180653
40. Cheng K.H., Chu C.S., Lee K.T. Lin T.-H., Hsieh C.-C., Chiu C.-C., Voon W.-C., Sheu S.-H., Lai W.-T. Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int. J. Obes. (Lond.). 2008; 32: 268–274. doi: 10.1038/sj.ijo.0803726
41. Payne G.A., Borbouse L., Kumar S., Neeb Z., Alloosh M., l Sturek M., Tune J.D. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1711–1717. doi 10.1161/atvbaha.110.210070
42. Greenstein A.S., Khavandi K., Withers S.B., Sonoyama K., Clancy O., Jeziorska M., Laing I., Yates A.P., Pemberton P.W., Malik R.A., Heagerty A.M. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation. 2009; 119: 1661–1670. doi: 10.1161/circulationaha.108.821181
43. Kopjar T., Dashwood M.R. Endoscopic versus “NoTouch” saphenous vein harvesting for coronary artery bypass grafting: a trade-off between wound healing and graft patency. Angiology. 2016; 67: 121–132. doi: 10.1177/0003319715584126
44. Dashwood M.R., Dooley A., Shi-Wen X., Abraham D.J., Dreifaldt M., Souza D.S.R. Perivascular fat-derived leptin: a potential role in improved vein graft performance in coronary artery bypass surgery. Interact. Cardiovasc. Thorac. Surg. 2011; 12: 170–173. doi: 10.1510/icvts.2010.247874
45. Khan T., Hamilton M.P., Mundy D.I., Chua S.C., Scherer P.E. Impact of simvastatin on adipose tissue: pleiotropic effects in vivo. Endocrinology. 2009; 150: 5262–5272. doi: 10.1210/en.2009-0603
46. Wojcicka G., Jamroz-Wisniewska A., Atanasova P., Chaldakov G.N., Chylińska-Kula B., Bełtowski J. Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. Pharmacol. Res. 2011; 63: 68–76. doi: 10.1016/j.phrs.2010.10.011
47. Синицкий М.Ю., Понасенко А.В., Груздева О.В. Генетический профиль и секретом адипоцитов висцеральной и подкожной жировой ткани у пациентов с сердечно-сосудистыми заболеваниями. Компл. пробл. сердечно-сосудистых заболеваний. 2017; 3: 155–165.
48. Shimizu I., Aprahamian T., Kikuchi R. et al. Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. 2014; 124: 2099–2112. doi: 10.1172/JCI71643Е
49. Padilla J., Jenkins N.T., Vieira-Potter V.J., Laughlin M.H. Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013; 304: R543–R552. doi: 10.1152/ajpregu.00567.2012
50. Weston A.H., Egner I., Dong Y., Porter E.L., Heagerty A.M., Edwards G. Stimulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin. Br. J. Pharmacol. 2013; 169: 1500–1509. doi: 10.1111/bph.12157
51. Withers S.B, Simpson L., Fattah S., Werner M.E., Heagerty A.M. cGMP-dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue. Cardiovasc. Res. 2013; 101 (1): 130–137. doi: 10.1093/cvr/cvt229
52. Kroller-Schon S., Jansen T., Hauptmann F., Schüler A., Heeren T., Hausding M., Oelze M., Viollet B., Keaney J.F., Wenzel P., Daiber A., Münzel T., Schulz E. alpha1AMP-activated protein kinase mediates vascular protective effects of exercise. Arterioscler. Thromb. Vasc. Biol. 2012; 32: 1632–1641. doi: 10.1161/ATVBAHA.111.243980
53. Fentz J., Kjobsted R., Kristensen C.M, Hingst J.R., Birk J.B., Gudiksen A., Foretz M., Schjerling P., Viollet B., Pilegaard H., Wojtaszewski J.F. AMPKalpha is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2015; 309: E900–E914. doi: 10.1152/ajpendo.00157.2015
54. Cao S., Li B., Yi X., Chang B, Zhu B, Lian Z, Zhang Z, Zhao G, Liu H, Zhang H. Effects of exercise on AMPK signaling and downstream components to PI3K in rat with type 2 diabetes. PLoS One. 2012; 7: e51709. doi: 10.1371/journal.pone.0051709
55. Boa B.C., Yudkin J.S., van Hinsbergh V.W., Bouskela E., Eringa E.C. Exercise effects on perivascular adipose tissue: endocrine and paracrine determinants of vascular function. Br. J. Pharmacol. 2017; 174: 3466–3481. doi: 10.1111/bph.13732
56. Min S.Y., Kady J., Nam M., Rojas-Rodriguez R., Berkenwald A., Kim J.H., Noh H.-L., Kim J.K., Cooper M.P., Fitzgibbons T., Brehm M.A., Corvera S. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 2016; 22: 312–318. doi: 10.1038/nm.4031
57. Singh P., Zhang Y., Sharma P., Covassin N., Soucek F., Friedman P.A., Somers V.K. Statins decrease leptin expression in human white adipocytes. Physiol. Rep. 2018; 6 (2). doi: 10.14814/phy2.13566
58. Yano M., Matsumura T., Senokuchi T., Ishii N., Murata Y., Taketa K., Motoshima H., Taguchi T., Sonoda K., Kukidome D., Takuwa Y., Kawada T., Brownlee M., Nishikawa T., Araki E. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ. Res. 2007; 25; 100 (10): 1442–1451. doi: 10.1161/01.RES.0000268411.49545.9c
59. Дылева Ю.А., Груздева О.В., Белик Е.В., Акбашева О.Е., Учасова Е.Г., Бородкина Д.А., Синицкий М.Ю., Сотников А.В., Козырин К.А., Каретникова В.Н., Барбараш О.Л. Экспрессия гена и содержание адипонектина в жировой ткани у пациентов с ишемической болезнью сердца. Биомед. химия. 2019; 65 (3): 239–244. doi: 10.18097/pbmc20196503239
60. Koh K.K., Sakuma I., Quon M.J. Differential metabolic effects of distinct statins. Atherosclerosis. 2010; 215: 1–8. 79. doi: 10.1016/j.atherosclerosis.2010.10.036
61. Sun Y., Li J., Xiao N., Wang M., Kou J., Qi L., Huang F., Liu B., Liu K. Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacol Res. 2014; 89: 19–28. doi: 10.1016/j.phrs.2014.07.006.
62. Chen Y., Xu X., Zhang Y., Liu K., Kou J. Diosgenin regulates adipokine expression in perivascular adipose tissue and ameliorates endothelial dysfunction via regulation of AMPK. J. Steroid. Biochem. Mol. Biol. 2016; 155: 155–165. doi: 10.1016/j.jsbmb.2015.07.005
63. Rena G., Hardie D.G., Pearson E.R. The mechanisms of action of metformin. Diabetologia. 2017; 60: 1577–1585. doi: 10.1007/s00125-017-4342-z
64. Zhang C.S., Li M., Ma T., Zong Y. Metformin activates AMPKthrough the lysosomal pathway. Cell Metab. 2016; 24: 521–552. doi: 10.1016/j.cmet.2016.09.003
65. Vendrell J., Bekay R., Peral B,. García-Fuentes E., Megia A., Macías-González M., Real J.М., Jiménez-Gómez Y., Escoté X., Pachón G., Simó R., Selva D.M., Malagón M.M., Tinahones F.J. Study of the Potential Association of Adipose Tissue GLP-1 Receptor with Obesity and Insulin Resistance. Endocrinology. 2011; 152: 11 (1): 4072–4079, doi: 10.1210/en.2011-1070
66. Cantini G., Mannucci E., Luconi M. Perspectives in GLP-1 research: new targets, new receptors. Trends Endocrinol. Metab. 2016; 27: 427–438. doi: 10.1016/j.tem.2016.03.017