The effects of the “youth protein” GDF11 and “aging proteins” ccL11, GDF15, JAM-A on cardiohemodynamics in women with essential hypertension

Objective. To identify the effects of youth and aging proteins — GDF11, CCL11, GDF15, JAM-A on cardiohemodynamics in healthy and hypertensive women.

Design and methods. The study involved 102 women. The control group consisted of 30 healthy women. Hypertensives were divided into 2 groups. The first (HTN-1) included 37 women with stage II hypertension (HTN) who received antihypertensive therapy. The second group (HTN-2) included patients who received antihypertensive drugs and regularly underwent kinesitherapy for 2-3 years. The enzyme immunoassay (ELISA) method was performed to determine the levels of GDF11, GDF15, JAM-A and CCL11 proteins. All subjects underwent echocardiography and dynamic light scattering (DLS).

Results. In healthy women, we found a positive correlation between the GDF15 proteins and JAM-A and blood pressure (BP). The GDF11/GDF15 ratio negatively correlated with BP level. In HTN-1 group, a negative relationship was found between the GDF15 level and the mean and pulse systolic pressure. In HTN-2 group, a negative relationship was found between CCL11 protein and pulse pressure, as well as the GDF15/CCL11 ratio and diastolic and positive correlation with the pulse pressure. In healthy subjects, no significant correlations were found between the studied proteins and cardiovascular functions, but GDF11/CCL11 ratio positively correlated with echocardiographic indices: the final systolic and impact volumes. In HTN-2 group, a positive relationship was found between the GDF11/GDF15 ratio and the minute volume, as well as GDF15/CCL11 and systolic shortening. The absolute values of hemodynamic indices (HI) in HTN-1 group were lower than in the control group, indicating a violation of the microcirculation with the trend towards the higher velocities. In HTN-2 group, hemodynamic parameters were close to those in the control group. In healthy individuals, HTN-1 and HTN-2 groups, dozens correlations were found between the studied proteins, their ratios, and various hemodynamic and oscillatory indices.

Conclusions. The levels of the “youth protein” GDF11 and the “aging proteins” GDF15, CCL11, JAM-A, as well as their ratios, exhibit positive and negative relationships with BP and cardiohemodynamic functions. At the same time, the effect of GDF11 and its predominance over CCL11, GDF15 and JAM-A is mostly adaptive.

1. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013; 153(4):828-839. doi:10.1016/j.cell.2013.04.015

2. Castellano JM. Blood-based therapies to combat aging. Gerontology. 2019;65(1):84-89. doi:10.1159/000492573

3. Kuznik BI, Davydov SO, Stepanov AV, Smolyakov YN, Guseva ES. The value of “youth protein” — GDF11 and “proteins of old age” — GDF15, CCL11, JAM-A in the regulation of blood pressure in healthy and hypertensive women. Patologi-cheskaya Fiziologiya i Eksperimental’naya Terapiya = Pathological Physiology and Experimental Therapy. 2018;2:46-52. doi:10.25557/0031-2991.2018.02.46-52. In Russian.

4. Kuznik BI, Khavinson VKh, Davydov SO, Stepanov AV. The proteins of youth and old age. The proteins are the markers of cellular aging and predictors of life expectancy. Palmarium, academic publishing. 2017. 285 p. In Russian.

5. Khavinson VKh, Kuznik BI, Tarnovskaya SI, Linkova NS. GDF11 Protein as a Geroprotector. Biology Bulletin Reviews. 2016;6(2):141-148. doi:10.1134/S207908641602002X

6. Tito A, Barbulova A, Zappelli C, Leone M, Ruvo M, Mercu-rio FA et al. The growth differentiation factor 11 is involved in skin fibroblast ageing and is induced by a preparation of peptides and sugars derived from plant cell cultures. Mol Biotechnol. 2019;61 (3):209-220. doi:10.1007/s12033-019-00154-w

7. Zhang C, Wang Y, Ge Z, Lin J, Liu J, Yuan X et al. GDF11 attenuated ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC through downregulating CCL11 in mice. Curr Mol Med. 2018;18(10):661-671. doi:10.2174/1566524019666190204112753

8. Kuznik BI, Davydov SO, Guseva ES, Stepanov AV, Smolyakov YN, Tsybikov NN et al. The relationship of individual leukocyte populations and the activity of the cardiovascular system in women suffering from hypertension. Sistemnye Gipertenzii = Systemic Hypertension. 2017;14(4):32-37. doi:10.26442/2075-082X_14.4.32-37. In Russian.

9. Kuznik BI, Davydov SO, Stepanov AV, Guseva ES, Smolyakov YN, Fayn IV. Adhesive JAM-A molecule and pathogenetic mechanisms of hypertension formation. Arterial’naya Gipertenziya = Arterial Hypertension. 2018:24(3):293-302. doi:10.18705/1607-419X-2018-24-3-293-302. In Russian.

10. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90-94. doi:10.1038/nature10357

11. Lalli MA, Bettcher BM, Arcila ML. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer’s disease. Mol Psychiatry. 2015;20 (11):1294-1300. doi:10.1038/mp.2015.131

12. Stuart MJ, Singhal G, Baune BT. Systematic review of the neurobiological relevance of chemokines to psychiatric disorders. Front Cell Neurosci. 2015;9:357. doi:10.3389/fncel.2015.00357

13. Emanuele E, Falcone C, D’Angelo A, Minoretti P, Buzzi MP, Bertona M et al. Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease. Atherosclerosis. 2006;186(1):140-145. doi:10.1016/j.atherosclerosis. 2005.07.002

14. Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F, Wu L et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell. 2010;9(6):1057-1064. doi:10.1111/j.1474-9726.2010.00629.x

15. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: The Rancho Bernardo Study. Circulation. 2 011;123 (19):2101—2110. doi:10.1161/CIRCULATIONAHA.n0.979740

16. Maetzler W, Deleersnijder W, Hanssens V, Bernard A, Brockmann K, Marquetand J et al. GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia. PLoS One. 2016;11(3):e0149349. doi:10.1371/journal.pone.0149349

17. Jiang J, Wen W, Sachdev PS. Macrophage inhibitory cytokine-1/growth differentiation factor 15 as a marker of cognitive ageing and dementia. Curr Opin Psychiatry. 2016;29(2):181—186. doi:10.1097/YC0.0000000000000225

18. Berezin AE. Diabetes mellitus related biomarker: the predictive role of growth-differentiation factor-15. Diabetes Metab Syndr. 2016;10(1Suppl1):S154-S157. doi.org/10.1016/j.dsx.2015.09.016

19. Bonaterra GA, Zugel S, Thogersen J, Walter SA, Haberkorn U, Strelau J et al. Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent i nflammatory response to vascular injury. JAm HeartAssoc. 2012;1 (6):1—14. doi.org/10.1161/JAHA.112.002550

20. Xu H, Oliveira-Sales EB, McBride F, Liu B, Hewinson J, Toward M et al. Upregulation ofjunctional adhesion molecule-A is a putative prognostic marker of hypertension. Cardiovasc Res. 2012;96(3):552-560. doi:10.1093/cvr/cvs273

21. Davydov SO, Stepanov AV, Kuznik BI, Guseva ES. The effect of kinesitherapy on the level of the jam-a adhesive molecule in patients with essential hypertension. Vestnik Vosstanovitel’noj Meditsiny = Bulletin of Restorative Medicine. 2017;5:33-37. In Russian.

22. Guseva ES, Davydov SO, Kuznik BI, Smolyakov YN, Stepanov AV, Fayn IV et al. The role of differentiation growth factor 11 (GDF11) in the regulation of lipid metabolism and cardiohemodynamic functions in patients with essential hypertension and moderate exercise. Rossijskij Kardiologicheskij Zhurnal = Russian Journal of Cardiology. 2018;4:93-98. doi: 10.15829/1560-4071-2018-4-93-98. In Russian.

23. Kuznik BI, Davydov SO, Smolyakov YN, Stepanov AV, Guseva ES, Fain IV et al. The role of proteins “youth and old age” in the pathogenesis of hypertension. Successes of Gerontology. 2018;31(3):362-367. In Russian.

24. Kuznik BI, Davydov SO, Roytman EV, Smolyakov YN, Guseva ES, Stepanov AS et al. Protein GDF15 and the state of cardiohemodynamic functions in women with hypertension. Vrach = Doctor. 2019;30(1):3-9. doi:10.29296/25877305-2019-01-01. In Russian.

25. Ahn ST, Suh SI, Moon H, Hyun C. Evaluation of growth differentiation factor 11 (GDF11) levels in dogs with chronic mitral valve insufficiency. Can J Vet Res. 2016;80(1):90-92.

26. Roy-O’Reilly M, Ritzel RM, Conway SE, Staff I, Fortunato G, McCullough LD. CCL11 (Eotaxin-1) levels predict long-term functional outcomes in patients following ischemic stroke. Transl Stroke Res. 2017;8(6):578-84. doi:10.1007/s12975-017-0545-3

27. Johnen H, Kuffner T, Brown DA, Wu BJ, Stocker R, Breit SN. Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE (-/-) mice from the development of atherosclerosis. Cardiovascular Pathology. 2012;21(6):499-505. doi:10.1016/j.carpath.2012.02.003

28. Fine I, Kuznik B, Kaminsky A et al. New noninvasive index for evaluation of the vascular age of healthy and sick people. J Biomed Opt. 2012;17(8):087002-1. doi:10.1117/1.JBO.17.8.087002

29. Fine I, Kaminsky AV, Kuznik BI, Kustovsjya EM, Maximova OG, Shenkman L. A new sensor for stress measurement based on blood flow fluctuations. Dynamics and Fluctuations in Biomedical Photonics XII, edited by Valery V. Tuchin. SPIE Press. 2016;9707:970705. doi:10.1117/12.2212866

30. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2018. [Electronic resource] Available at: https://www.R-project.org (Accessed 23 January 2019).

31. Kuznik BI, Linkova NS, Kolchina NV, Kukаnova EO, Khavinson VKh. The family of JAM molecules and their role in the regulation of physiological and pathological processes. Uspekhi Fiziologicheskih Nauk = Successes Fiziol. Sciences. 2016;47(4):76-98. In Russian.

32. Ong KL, Leung RY, Babinska A, Salifu MO, Ehrlich YH, Kornecki E et al. Elevated plasma level of soluble F11 receptor/ junctional adhesion molecule-A (F11R/JAM-A) in hypertension. Am J Hypertens. 2009;22(5):500-505.doiorg/10.1038/ajh.2009.23

33. Schmitt MM, Fraemohs L, Hackeng TM, Weber C, Koenen RR. Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution. Atherosclerosis. 2014;234(2):254-264. doi:10.1016/j.atherosclerosis.2014.03.014

34. Julien C. The enigma of Mayer waves: facts and models. Cardiovascular Research. 2006;(70)1:12-21. doi:10.1016/j.cardiores.2005.11.008

35. Khavinson VKh, Kuznik BI, Ryzhak GA, Linkova NS, Kozina LS, Sall TS. “Protein of old age” CCl11, “protein of youth” GDF11 and their role in age-related pathology. Uspekhi Gerontologii = Successes of Gerontology. 2016; 29(5):722-731. In Russian.

36. Schmitt MM, Megens RT, Zernecke A, Bidzhekov K, van den Akker NM, Rademakers T et al. Endothelial junctional adhesion molecule-a guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation. 2014;129(1):66-76. doi:10. 1161/CIRCULATIONAHA.113.004149

37. Khavinson VKh, Kuznik BI, Tarnovskaya SI, Linkova NS. Peptides and CCL11 and HMGB1 as molecular markers of aging: literature review and own data. Adv Gerontol. 2015;5(3):133-140. doi:10.1134/S2079057015030078

38. Cho SY, Roh HT. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men. J Phys Ther Sci. 2016;28(4):1355-1358.

39. Brack AS. Ageing of the heart reversed by youthful systemic factors! EMBO J. 2013;32(16):2189-2190. doi:10.1038/emboj.2013.162

40. Wang X, Yang X, Sun K, Chen J, Song X, Wang H et al. The haplotype of the growth-differentiation factor 15 gene is associated with left ventricular hypertrophy in human essential hypertension. Clin Sci. 2009;118(2):137-145. doi: 10.1042/CS20080637

41. Ushakov AV, Ivanchenko VS, Gagarina AA. Features of blood pressure profile and heart rate variability in patients with arterial hypertension, depending on the level of physical activity and psycho-emotional stress. Rossijskij Kardiologicheskij Zhurnal = Russian Journal of Cardiology. 2017;4:23-28. doi:10.15829/1560-4071-2017-4-23-28 In Russian.

42. Roitman E. V. Clinical hemorheology. Tromboz, Gemostaz i Reologiya = Thrombosis, Hemostasis and Rheology. 2003;3:13-27. In Russian.

43. Prestgaard E, Mariampillai J, Engeseth K, Erikssen J, Bodegard J, Liest0l K et al. Change in cardiorespiratory fitness and risk of stroke and death. Stroke. 2019;50(1):155-161. doi:10.1161/STROKEAHA.118.021798

44.