Serotonin, 5-HIAA, and membrane serotonin transporter in blood as biomarkers of familial hypercholesterolemia in immature low-density lipoprotein receptor-deficient mice
- 作者: Nigmatullina R.R.1, Sadykova D.I.1, Slastnikova E.S.1,2, Abzaletdinova G.F.1
-
隶属关系:
- Kazan State Medical University Ministry of Health of Russia
- Children’s Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
- 期: 卷 23, 编号 4 (2025)
- 页面: 30-38
- 栏目: Original research
- URL: https://journals.eco-vector.com/1728-2918/article/view/689095
- DOI: https://doi.org/10.29296/24999490-2025-04-05
- ID: 689095
如何引用文章
详细
Introduction. Cardiovascular diseases are the main cause of death and disability in the world population. Serotonin plays a significant role in the development and progression of atherosclerotic processes due to its two classical functions – platelet aggregation and smooth muscle cell proliferation.
The aim of the study was to evaluate changes in the level of serotonin, its metabolite and membrane transporter of serotonin in blood plasma and platelets as a biomarker of atherosclerotic vascular lesions.
Material and methods. The study was conducted on 48 C57BL/6JGpt-Ldlrem1Cd82/Gpt (Ldlr+/–) mice aged 5–7 weeks (main group) and 36 C57BL/6 mice of the corresponding age and sex (control group). Laboratory research methods included: complete blood count, determination of total cholesterol level in blood serum, determination of serotonin concentration, its metabolite in blood plasma and platelets, membrane transporter in platelets.
Results. In mice with low-density lipoprotein receptor deficiency, a significant increase in the level of total cholesterol in the blood serum was determined. The concentration of serotonin and its metabolite in blood plasma and platelets, membrane transporter was statistically significantly higher in animals of the main group. Positive correlations were found between the concentration of serotonin and its metabolite, transporter, total cholesterol and a negative correlation with the level of platelets.
Conclusion. Serotonin, its metabolite and transporter may become new biomarkers for the diagnosis of cardiovascular diseases and therapeutic targets for the treatment and prevention of progression of atherosclerotic vascular lesions in children and adults.
全文:

作者简介
Razina Nigmatullina
Kazan State Medical University Ministry of Health of Russia
编辑信件的主要联系方式.
Email: razinar@mail.ru
ORCID iD: 0000-0002-4686-1231
Doctor of Biological Sciences, Professor of the Department of Normal Physiology
俄罗斯联邦, Butlerova St., 49, Kazan, 420012Dinara Sadykova
Kazan State Medical University Ministry of Health of Russia
Email: sadykovadi@mail.ru
ORCID iD: 0000-0002-6662-3548
Head of the Department of Hospital Pediatrics, Professor
俄罗斯联邦, Butlerova St., 49, Kazan, 420012Evgeniya Slastnikova
Kazan State Medical University Ministry of Health of Russia; Children’s Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan
Email: e.slastnikova@mail.ru
ORCID iD: 0000-0002-1732-7443
Candidate of Medical Sciences, Department of Hospital Pediatrics, Head of the Consultation Office of the Republican Center for Lipidology for Children
俄罗斯联邦, Butlerova St., 49, Kazan, 420012; Orenburgsky Tract St., 140, Kazan, 420138Gulnaz Abzaletdinova
Kazan State Medical University Ministry of Health of Russia
Email: gulnaz.abzaletdinova@mail.ru
ORCID iD: 0009-0007-1824-0677
Student of the Pediatric Faculty
俄罗斯联邦, Butlerova St., 49, Kazan, 420012参考
- Vaduganathan M., Mensah G.A, Turco J.V, Fuster V., Roth G.A. The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health. J. Am. Coll. Cardiol. 2022; 80 (25): 2361–71. doi: 10.1016/j.jacc.2022.11.005
- Садыкова Д.И., Салахова К.Р., Галимова Л.Ф., Сластникова Е.С., Халиуллина Ч.Д. Семейная гиперхолестеринемия у детей. Современное состояние проблемы. Вопросы современной педиатрии. 2023; 22 (3): 231–40. [Sadykova D.I., Salakhova K.R., Galimova L.F., Slastnikova E.S., Khaliullina Ch.D. Familial Hypercholesterolemia in Children. The Current State of the Problem. Current Pediatrics. 2023; 22 (3): 231–40. https://doi.org/10.15690/vsp.v22i3.2576 (In Russian)].
- Capra M.E., Biasucci G., Banderali G., Vania A., Pederiva C. Diet and Lipid-Lowering Nutraceuticals in Pediatric Patients with Familial Hypercholesterolemia. Children (Basel). 2024; 11 (2): 250. doi: 10.3390/children11020250
- Emini Veseli B., Perrotta P., De Meyer G., Roth L., Van der Donckt C., Martinet W. De Meyer G. Animal models of atherosclerosis. Eur J Pharmacol. 2017; 816: 3–13. doi: 10.1016/j.ejphar.2017.05.010
- Zhao Y., Qu H., Wang Y., Xiao W., Zhang Y., Shi D. Small rodent models of atherosclerosis. Biomed Pharmacother. 2020; 129: 110426. doi: 10.1016/j.biopha.2020.110426
- Oppi S., Lüscher T.F., Stein S. Mouse Models for Atherosclerosis Research-Which Is My Line? Front Cardiovasc Med. 2019; 6: 46. doi: 10.3389/fcvm.2019.00046.
- Chen S.J., Cho R.L., Yeh S.H., Tsai M.C., Chuang Y.P., Lien C.F., Chiu C.H., Yeh Y.W., Lin C.S., Ma K.H. Pitavastatin attenuates hypercholesterolemia-induced decline in serotonin transporter availability. Lipids Health Dis. 2024; 23 (1): 250. doi: 10.1186/s12944-024-02236-4
- Ежов М.В., Бажан С.С., Ершова А.И., Мешков А.Н., Соколов А.А., Кухарчук В.В., Гуревич В.С., Воевода М.И., Сергиенко И.В., Шахтшнейдер Е.В., Покровский С.Н., Коновалов Г.А., Леонтьева И.В., Константинов В.О., Щербакова М.Ю., Захарова И.Н., Балахонова Т.В., Филиппов А.Е., Ахмеджанов Н.М., Александрова О.Ю., Липовецкий Б.М. Клинические рекомендации по семейной гиперхолестеринемии. Атеросклероз. 2019; 15 (1): 58–98. [Ezhov M.V., Bazhan S.S., Ershova A.I., Meshkov A.N., Sokolov A.A., Kukharchuk V.V., Gurevich V.S., Voevoda M.I., Sergienko I.V., Shakhtshneider E.V., Pokrovsky S.N., Konovalov G.A., Leontyeva I.V., Konstantinov V.O., Shcherbakova M.Yu., Zakharova I.N., Balakhonova T.V., Filippov A.E., Akhmedzhanov N.M., Aleksandrova O.Yu., Lipovetsky B.M. Clinical guidelines for familial hypercholesterolemia. Ateroscleroz. 2019; 15 (1): 58–98 (In Russian)].
- Beheshti S.O., Madsen C.M., Varbo A., Nordestgaard B.G. Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects. J. Am. Coll. Cardiol. 2020; 75 (20): 2553–66. doi: 10.1016/j.jacc.2020.03.057
- Medeiros A.M., Alves A.C., Aguiar P., Bourbon M. Pediatric Investigators of the Portuguese Familial Hypercholesterolemia Study. Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia. J. Lipid Res. 2014; 55 (5): 947–55. doi: 10.1194/jlr.P043182
- Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L., Chapman M.J. et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41 (1): 111–88. doi: 10.1093/eurheartj/ehz455
- Rieder M., Gauchel N., Bode C., Duerschmied D. Serotonin: a platelet hormone modulating cardiovascular disease. J. Thromb Thrombolysis. 2021; 52 (1): 42–7. doi: 10.1007/s11239-020-02331-0
- Brenner B., Harney J.T., Ahmed B.A., Jeffus B.C., Unal R., Mehta J.L., Kilic F. Plasma serotonin levels and the platelet serotonin transporter. J. Neurochem. 2007; 102 (1): 206–15. doi: 10.1111/j.1471-4159.2007.04542.x
- Mercado C.P., Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010; 10 (4): 231–41. doi: 10.1124/mi.10.4.6
- Kanova M., Kohout P. Serotonin-Its Synthesis and Roles in the Healthy and the Critically Ill. Int. J. Mol. Sci. 2021; 22 (9): 4837. doi: 10.3390/ijms22094837
- Neumann J., Hofmann B., Dhein S., Gergs U. Cardiac Roles of Serotonin (5-HT) and 5-HT-Receptors in Health and Disease. Int. J. Mol. Sci. 2023; 24 (5): 4765. doi: 10.3390/ijms24054765
- Sadykova D., Nigmatullina R., Salakhova K., Slastnikova E., Galimova L., Khaliullina Ch., Valeeva I. Membrane Transporter of Serotonin and Hypercholesterolemia in Children. Int. J. Mol. Sci. 2024; 25 (2): 767. doi: 10.3390/ijms25020767
- Ma Y., Liang X., Li C., Li R., Tong X., Zhang R., Shan X., Yang J., Ma X., Lu W., Li R., Fu J. 5-HT2A Receptor and 5-HT Degradation Play a Crucial Role in Atherosclerosis by Modulating Macrophage Foam Cell Formation, Vascular Endothelial Cell Inflammation, and Hepatic Steatosis. J. Atheroscler Thromb. 2022; 29 (3): 322–36. doi: 10.5551/jat.58305
- Жукова Г.В., Франциянц Е.М., Шихлярова А.И., Каплиева И.В., Трепитаки Л.К., Качесова П.С., Галина А.В., Ушакова Н.В., Шалашная Е.В., Ишонина О.Г. Особенности показателей крови и адаптационного статуса мышей линий Balb/c и С57BL/6 при отсутствии специальных воздействий. Южно-Российский онкологический журнал. 2023; 4 (4): 44–56. [Zhukova G.V., Frantsiyants E.M., Shikhlyarova A.I., Kaplieva I.V., Trepitaki L.K., Kachesova P.S., Galina A.V., Ushakova N.D., Shalashnaya E.V., Ishonina O.G. Features of blood parameters and adaptational status of Balb/c and C57Bl/6 mice lines in the absence of special influences. South Russian J. of Cancer. 2023; 4 (4): 44–56. https://doi.org/10.37748/2686-9039-2023-4-4-5 (In Russian)].
- Barrios M., Rodriguez-Acosta A., Gil A., Salazar A.M., Taylor P., Sánchez E.E., Arocha-Piñango C.L., Guerrero B. Comparative hemostatic parameters in BALB/c, C57BL/6 and C3H/He mice. Thromb Res. 2009; 124 (3): 338–43. doi: 10.1016/j.thromres.2008.11.001
- Liao M., Liu L., Bai L., Wang R., Liu Y., Zhang L., Han J., Li Y., Qi B. Correlation between novel inflammatory markers and carotid atherosclerosis: A retrospective case-control study. PLoS One. 2024; 19 (5): e0303869. doi: 10.1371/journal.pone.0303869
- Vikenes K., Farstad M., Nordrehaug J.E. Serotonin is associated with coronary artery disease and cardiac events. Circulation. 1999; 100 (5): 483–9. doi: 10.1161/01.cir.100.5.483
- John Jayakumar J., Panicker M M. The roles of serotonin in cell adhesion and migration, and cytoskeletal remodeling. Cell Adh Migr. 2021; 15 (1): 261–71. doi: 10.1080/19336918.2021.1963574
- Napoli C., Lerman L.O. Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia. Mayo Clin Proc. 2001; 76 (6): 619–31. doi: 10.4065/76.6.619
- Morotti A., Barale C., Melchionda E., Russo I. Platelet Redox Imbalance in Hypercholesterolemia: A Big Problem for a Small Cell. Int. J. Mol. Sci. 2022; 23 (19): 11446. doi: 10.3390/ijms231911446
- Ziu E., Mercado C.P., Li Y., Singh P., Ahmed B.A., Freyaldenhoven S., Lensing S., Ware J., Kilic F. Down-regulation of the serotonin transporter in hyperreactive platelets counteracts the pro-thrombotic effect of serotonin. J. Mol. Cell. Cardiol. 2012; 52 (5): 1112–21. doi: 10.1016/j.yjmcc.2012.02.004
- Walther D.J., Peter J.U., Winter S., Höltje M., Paulmann N., Grohmann M., Vowinckel J., Alamo-Bethencourt V., Wilhelm C.S., Ahnert-Hilger G., Bader M. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell. 2003; 115 (7) :851–62. doi: 10.1016/s0092-8674(03)01014-6
- Yu Y., Cai Y., Yang F., Yang Y., Cui Z., Shi D., Bai R. Vascular smooth muscle cell phenotypic switching in atherosclerosis. Heliyon. 2024; 10 (18): 37727. doi: 10.1016/j.heliyon.2024.e37727
- Gomez D., Owens G.K. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res. 2012; 95 (2): 156–64. doi: 10.1093/cvr/cvs115
- Su C., Lu Y., Wang Z., Guo J., Hou Y., Wang X., Qin Z., et al. Atherosclerosis: The Involvement of Immunity, Cytokines and Cells in Pathogenesis, and Potential Novel Therapeutics. Aging Dis. 2023; 14 (4): 1214–42. doi: 10.14336/AD.2022.1208
- Déglise S., Bechelli C., Allagnat F. Vascular smooth muscle cells in intimal hyperplasia, an update. Front Physiol. 2023; 13: 1081881. doi: 10.3389/fphys.2022.1081881
- Nemecek G.M., Coughlin S.R., Handley D.A, Moskowitz M.A. Stimulation of aortic smooth muscle cell mitogenesis by serotonin. Proc Natl Acad Sci USA. 1986; 83 (3): 674–8. doi: 10.1073/pnas.83.3.674
- Watada S., Harada H., Matsubara K., Obara H., Matsumoto K., Ando N., Kitagawa Y. Effect of sarpogrelate hydrochloride, a 5-hydroxytryptamine2 receptor antagonist, on allograft arteriosclerosis after aortic transplantation in rats. Transpl Immunol. 2013; 29 (1): 162–6. doi: 10.1016/j.trim.2013.07.001
- Hayashi T., Sumi D., Matsui-Hirai H., Fukatsu A., Arockia Rani P., Kano H., Tsunekawa T., Iguchi A.. Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism. Atherosclerosis. 2003; 168 (1): 23–31. doi: 10.1016/s0021-9150(03)00054-6
- Koba S., Pakala R., Watanabe T., Katagiri T., Benedict C.R. Vascular smooth muscle proliferation: synergistic interaction between serotonin and low density lipoproteins. J. Am. Coll. Cardiol. 1999; 34 (5): 1644–51. doi: 10.1016/s0735-1097(99)00349-6
- Shan J., Khelashvili G., Mondal S., Mehler E.L., Weinstein H. Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties. PLoS Comput Biol. 2012; 8 (4): e1002473. doi: 10.1371/journal.pcbi.1002473
- Fraer M., Kilic F. Serotonin: a different player in hypertension-associated thrombosis. Hypertension. 2015; 65 (5): 942–8. doi: 10.1161/HYPERTENSIONAHA.114.05061
- Deveau C.M., Rodriguez E., Schroering A., Yamamoto B.K. Serotonin transporter regulation by cholesterol-independent lipid signaling. Biochem Pharmacol. 2021; 183: 114349. doi: 10.1016/j.bcp.2020.114349
- Ferraro M., Masetti M., Recanatini M., Cavalli A., Bottegoni G. Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics. PLoS One. 2016; 11 (12): e0166196. doi: 10.1371/journal.pone.0166196
- Scanlon S.M., Williams D.C., Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochemistry. 2001; 40 (35): 10507–13. doi: 10.1021/bi010730z
补充文件
