aterosklerozАтеросклерозAteroscleroz2078-256X2949-3633НИИТПМ-филиал ИЦиГ СО РАН10.15372/ATER20170406ateroskleroz-59Research ArticleОБЗОРЫREVIEWSБЕЛОК КЛОТО И АТЕРОСКЛЕРОЗKLOTHO PROTEIN AND ATHEROSCLEROSISТимощенкоО. В.TimoshchenkoO. V.lentis@yandex.ruНикитинЮ. П.NikitinYu. P.yuri-nikitin@ngs.ruНИИТПМ - филиал ИЦиГ СО РАНInstitute of Internal and Preventive Medicine - Branch of Federal Research Institute of Cytology and Genetics of SB RAS2017270920191343841Copyright © Тимощенко О.В., Никитин Ю.П., 20192019Тимощенко О.В., Никитин Ю.П.Timoshchenko O.V., Nikitin Y.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://ateroskleroz.elpub.ru/jour/article/view/59

В обзоре приводится анализ литературных данных о белке Клото. Открытие и углубленное изучение гена Клото и его белка расширили представление об естественном старении. Уровни сывороточного белка Клото уменьшаются с возрастом и при некоторых заболеваниях, связанных со старением, в частности, таких как остеопороз, артериальная гипертония, сахарный диабет, злокачественные новообразования, некоторые заболевания почек. Ряд экспериментальных публикаций дали основание предполагать, что белок Клото может оказывать влияние на функциональное состояние сосудистого эндотелия посредством подавления воспаления и окислительного стресса. По некоторым данным наблюдается снижение содержания в крови белка Клото при сердечно-сосудистых заболеваниях, однако такие данные малочисленны. Необходимы дальнейшие исследования в этом направлении для изучения возможных связей содержания белка Клото в сыворотке крови с атерогенезом. Новые знания в понимании этих процессов могут использоваться для поиска более эффективного подхода в лечебно-диагностической тактике сердечно-сосудистых заболеваний.

The review provides an analysis of the literature data on the Klotho protein. The discovery and in-depth study of the Klotho gene and its protein broadened the notion of natural aging. The levels of Klotho protein in serum decrease with age and with certain diseases associated with aging, in particular, such as osteoporosis, arterial hypertension, diabetes mellitus, malignant neoplasms, and certain kidney diseases. A number of experimental publications have suggested that the Klotho protein may affect the functional state of the vascular endothelium by suppressing inflammation and oxidative stress. According to some data a decrease the Klotho protein in blood is observed in cardiovascular diseases, but such data are scarce. Further studies are needed in this direction to determine possible relationships of the Klotho protein content in the blood serum with atherogenesis. New knowledge in understanding these processes can be used to find a more effective approach in the treatment and diagnostic tactics of cardiovascular diseases.

белок Клотоатеросклерозсердечно-сосудистые заболеванияKlotho proteinatherosclerosiscardiovascular diseasesReferencesSuga T., Kurabayashi M., Sando Y., Ohyama Y. et al. Disruption of the Klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life // Am. J. Respir. Cell. Mol. Biol. 2000. Vol. 22, N 1. P. 26-33.Suga T., Kurabayashi M., Sando Y., Ohyama Y. et al. Disruption of the Klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life // Am. J. Respir. Cell. Mol. Biol. 2000. Vol. 22, N 1. P. 26-33.Kamemori M., Ohyama Y., Kurabayashi M., Takahashi K. et al. Expression of Klotho protein in the inner ear // Hear Res. 2002. Vol. 171, N 1-2. P. 103-110.Kamemori M., Ohyama Y., Kurabayashi M., Takahashi K. et al. Expression of Klotho protein in the inner ear // Hear Res. 2002. Vol. 171, N 1-2. P. 103-110.Takahashi Y., Kuro-O M., Ishikawa F. Aging mechanisms // Proc. Natl. Acad. Sci. USA. 2000. Vol. 97, N 23. P. 12407-12408.Takahashi Y., Kuro-O M., Ishikawa F. Aging mechanisms // Proc. Natl. Acad. Sci. USA. 2000. Vol. 97, N 23. P. 12407-12408.Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H. et al. Mutation of the mouse Klotho gene leads to a syndrome resembling ageing // Nature. 1997. Vol. 390. P. 45-51.Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H. et al. Mutation of the mouse Klotho gene leads to a syndrome resembling ageing // Nature. 1997. Vol. 390. P. 45-51.Masuda H., Chikuda H., Suga T., Kawaguchi H. et al. Regulation of multiple ageing-like phenotypes by inducible Klotho gene expression in klotho mutant mice // Mech. Ageing. Dev. 2005. Vol. 126. P. 1274-1283.Masuda H., Chikuda H., Suga T., Kawaguchi H. et al. Regulation of multiple ageing-like phenotypes by inducible Klotho gene expression in klotho mutant mice // Mech. Ageing. Dev. 2005. Vol. 126. P. 1274-1283.Takeshita K., Fujimori T., Kurotaki Y., Honjo H. Sinoatrial node dysfunction and early unexpected death of mice with a defect of Klotho gene expression // Circulation. 2004. Vol. 109, N 14. P. 1776-1782.Takeshita K., Fujimori T., Kurotaki Y., Honjo H. Sinoatrial node dysfunction and early unexpected death of mice with a defect of Klotho gene expression // Circulation. 2004. Vol. 109, N 14. P. 1776-1782.Yahata K., Mori K., Arai H., Koide S. et al. Molecular cloning and expression of a novel klotho-related protein // J. Mol. Med. (Berl). 2000. Vol. 78, N 7. P. 389-394.Yahata K., Mori K., Arai H., Koide S. et al. Molecular cloning and expression of a novel klotho-related protein // J. Mol. Med. (Berl). 2000. Vol. 78, N 7. P. 389-394.Li S.A., Watanabe M., Yamada H., Nagai A. et al. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice // Cell. Struct. Funct. 2004. Vol. 29, N 4. P. 91-99.Li S.A., Watanabe M., Yamada H., Nagai A. et al. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice // Cell. Struct. Funct. 2004. Vol. 29, N 4. P. 91-99.Matsumura Y., Aizawa H., Shiraki-Iida T., Nagai R. et al. Identification of the human Klotho gene and its two transcripts encoding membrane and secreted klotho protein // Biochem. Biophys. Res. Commun. 1998. Vol. 242, N 3. P. 626-630.Matsumura Y., Aizawa H., Shiraki-Iida T., Nagai R. et al. Identification of the human Klotho gene and its two transcripts encoding membrane and secreted klotho protein // Biochem. Biophys. Res. Commun. 1998. Vol. 242, N 3. P. 626-630.Bloch L., Sineshchekova O., Reichenbach D., Reiss K. et al. Klotho is a substrate for alpha-, beta- and gamma-secretase // FEBS Lett. 2009. Vol. 583, N 19. P. 3221-3224.Bloch L., Sineshchekova O., Reichenbach D., Reiss K. et al. Klotho is a substrate for alpha-, beta- and gamma-secretase // FEBS Lett. 2009. Vol. 583, N 19. P. 3221-3224.Yamazaki Y., Imura A., Urakawa I. et al. Establishment of sandwich ELISA for soluble α-Klotho measurement: age-dependent change of soluble α-Klotho levels in healthy subjects // Biochem. Biophys. Res. Commun. 2010. Vol. 398. P. 513-518.Yamazaki Y., Imura A., Urakawa I. et al. Establishment of sandwich ELISA for soluble α-Klotho measurement: age-dependent change of soluble α-Klotho levels in healthy subjects // Biochem. Biophys. Res. Commun. 2010. Vol. 398. P. 513-518.Pedersen L., Pedersen S.M., Brasen C.L., Rasmussen L.M. Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays // Clin. Biochem. 2013. Vol. 46. P. 1079-1083.Pedersen L., Pedersen S.M., Brasen C.L., Rasmussen L.M. Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays // Clin. Biochem. 2013. Vol. 46. P. 1079-1083.Marçais C., Maucort-Boulch D., Drai J., Dantony E. et al. ARNOGENE Project. Circulating Klotho Associates With Cardiovascular Morbidity and Mortality During Hemodialysis // J. Clin. Endocrinol. Metab. 2017. Vol. 102, N 9. P. 3154-3161.Marçais C., Maucort-Boulch D., Drai J., Dantony E. et al. ARNOGENE Project. Circulating Klotho Associates With Cardiovascular Morbidity and Mortality During Hemodialysis // J. Clin. Endocrinol. Metab. 2017. Vol. 102, N 9. P. 3154-3161.Rubinek T., Wolf I., Modan-Moses D. The Longevity Hormone Klotho is a New Player in the Interacion of the Growth Hormone/Insulin-Like Growth Factor 1 Axis // Pediatr. Endocrinol. Rev. 2016. Vol. 14, N 1. P. 9-18.Rubinek T., Wolf I., Modan-Moses D. The Longevity Hormone Klotho is a New Player in the Interacion of the Growth Hormone/Insulin-Like Growth Factor 1 Axis // Pediatr. Endocrinol. Rev. 2016. Vol. 14, N 1. P. 9-18.De Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway // FEBS Lett. 2006. Vol. 580, N 24. P. 5753-5758.De Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway // FEBS Lett. 2006. Vol. 580, N 24. P. 5753-5758.Милованова Л.Ю., Милованов Ю.С., Козловская Л.В., Мухин Н.А. Значение морфогенетических белков FGF-23 и Klotho как предикторов прогноза хронической болезни почек // Терапевт. арх. 2014. Т. 86, № 4. С. 36-44.Милованова Л.Ю., Милованов Ю.С., Козловская Л.В., Мухин Н.А. Значение морфогенетических белков FGF-23 и Klotho как предикторов прогноза хронической болезни почек // Терапевт. арх. 2014. Т. 86, № 4. С. 36-44.Prié D., Beck L., Urena P., Friedlander G. Recent findings in phosphate homeostasis // Curr. Opin. Nephrol. Hypertens. 2005. Vol. 14, N 4. P. 318-324.Prié D., Beck L., Urena P., Friedlander G. Recent findings in phosphate homeostasis // Curr. Opin. Nephrol. Hypertens. 2005. Vol. 14, N 4. P. 318-324.Sabbagh Y., Giral H., Caldas Y., Levi M.et al. Intestinal phosphate transport // Adv. Chronic. Kidney Dis. 2011. Vol. 18, N 2. P. 85-90.Sabbagh Y., Giral H., Caldas Y., Levi M.et al. Intestinal phosphate transport // Adv. Chronic. Kidney Dis. 2011. Vol. 18, N 2. P. 85-90.Lu P., Boros S., Chang Q., Bindels R.J. et al. The beta-glucuronidase Klotho exclusively activates the epithelial Ca2+ channels TRPV5 and TRPV6 // Nephrol. Dial. Transplant. 2008. Vol. 23, N 11. P. 3397-3402.Lu P., Boros S., Chang Q., Bindels R.J. et al. The beta-glucuronidase Klotho exclusively activates the epithelial Ca2+ channels TRPV5 and TRPV6 // Nephrol. Dial. Transplant. 2008. Vol. 23, N 11. P. 3397-3402.Ohnishi M., Nakatani T., Lanske B., Razzaque M.S. Reversal of mineral ion homeostasis and soft-tissue calcification of Klotho knockout mice by deletion of vitamin D 1α-hydroxylase // Kidney Int. 2009. Vol. 75, N 11. P. 1166-1172.Ohnishi M., Nakatani T., Lanske B., Razzaque M.S. Reversal of mineral ion homeostasis and soft-tissue calcification of Klotho knockout mice by deletion of vitamin D 1α-hydroxylase // Kidney Int. 2009. Vol. 75, N 11. P. 1166-1172.Razzaque M.S., Lanske B. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice // Trends. Mol. Med. 2006. Vol. 12, N 7. P. 298-305.Razzaque M.S., Lanske B. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice // Trends. Mol. Med. 2006. Vol. 12, N 7. P. 298-305.Zhang S., Gillihan R., He N., Fields T., et al. Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease // Kidney Int. 2013. Vol. 84, N 4. P. 713-721.Zhang S., Gillihan R., He N., Fields T., et al. Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease // Kidney Int. 2013. Vol. 84, N 4. P. 713-721.Wang H.L., Xu Q., Wang Z. et al. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population // Clin. Chim. Acta. 2010. Vol. 411. P. 386-390.Wang H.L., Xu Q., Wang Z. et al. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population // Clin. Chim. Acta. 2010. Vol. 411. P. 386-390.Arking D.E., Krebsova A., Macek M., Sr, Macek M. et al. Association of human aging with a functional variant of Klotho // Proc. Natl. Acad. Sci. USA. 2002. Vol. 99. P. 856-861.Arking D.E., Krebsova A., Macek M., Sr, Macek M. et al. Association of human aging with a functional variant of Klotho // Proc. Natl. Acad. Sci. USA. 2002. Vol. 99. P. 856-861.Arking D.E., Becker D.M., Yanek L.R. et al. Klotho allele status and the risk of early-onset occult coronary artery disease // Am. J. Hum. Genet. 2003. Vol. 72. P. 1154-1156.Arking D.E., Becker D.M., Yanek L.R. et al. Klotho allele status and the risk of early-onset occult coronary artery disease // Am. J. Hum. Genet. 2003. Vol. 72. P. 1154-1156.Arking D.E., Atzmon G., Arking A. et al. Association between a functional variant of the Klotho gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity // Circ. Res. 2005. Vol. 96. P. 412-8.Arking D.E., Atzmon G., Arking A. et al. Association between a functional variant of the Klotho gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity // Circ. Res. 2005. Vol. 96. P. 412-8.Donate-Correa J., Mora-Fernández C., Martínez-Sanz R., Muros-de-Fuentes M. et al. Expression of FGF23/Klotho system in human vascular tissue // Int. J. Cardiol. 2013. Vol. 165, N 1. P. 179-183.Donate-Correa J., Mora-Fernández C., Martínez-Sanz R., Muros-de-Fuentes M. et al. Expression of FGF23/Klotho system in human vascular tissue // Int. J. Cardiol. 2013. Vol. 165, N 1. P. 179-183.Yao Y., Wang Y., Zhang Y., Liu C. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOSpathways // Lipids Health Dis. 2017. Vol. 16, N 1. P. 77.Yao Y., Wang Y., Zhang Y., Liu C. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOSpathways // Lipids Health Dis. 2017. Vol. 16, N 1. P. 77.Navarro-González J.F., Donate-Correa J., Muros de Fuentes M., Pérez-Hernández H. et al. Reduced Klotho is associated with the presence and severity of coronary artery disease // Heart. 2014. Vol. 100, N 1. P. 34-40.Navarro-González J.F., Donate-Correa J., Muros de Fuentes M., Pérez-Hernández H. et al. Reduced Klotho is associated with the presence and severity of coronary artery disease // Heart. 2014. Vol. 100, N 1. P. 34-40.Semba R.D. et al. Plasma Klotho and cardiovascular disease in adults // J. Am. Geriatr. Soc. 2011. Vol. 59. P. 1596-1601.Semba R.D. et al. Plasma Klotho and cardiovascular disease in adults // J. Am. Geriatr. Soc. 2011. Vol. 59. P. 1596-1601.Roberta S. Paula, Vinícius C. Souza, Wilcelly Machado-Silva, Bruno Ratier S. Almeida et al. Serum Klotho (but not haplotypes) associate with the post-myocardial infarction status of older adults // Clinics (Sao Paulo). 2016. Vol. 71, N 12. P. 725-732.Roberta S. Paula, Vinícius C. Souza, Wilcelly Machado-Silva, Bruno Ratier S. Almeida et al. Serum Klotho (but not haplotypes) associate with the post-myocardial infarction status of older adults // Clinics (Sao Paulo). 2016. Vol. 71, N 12. P. 725-732.Kitagawa M. et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease // PloS One. 2013. Vol. 8, N 2. E56695.Kitagawa M. et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease // PloS One. 2013. Vol. 8, N 2. E56695.Seiler S. et al. Associations of FGF-23 and s Klotho with cardiovascular outcomes among patients with CKD stages 2-4 // Clin. J. Am. Soc. Nephrol. 2014. Vol. 9. P. 1049-1058.Seiler S. et al. Associations of FGF-23 and s Klotho with cardiovascular outcomes among patients with CKD stages 2-4 // Clin. J. Am. Soc. Nephrol. 2014. Vol. 9. P. 1049-1058.

The authors declare that there are no conflicts of interest present.