Levels of marker lysosomal hydrolases in women with coronary heart disease depending on age and sex hormone level

Aim of the study was to evaluate the serum concentrations of three marker lysosomal hydrolases (cathepsin D, acid phosphatase (AP) and acid DNase (aDNAase)) in women with coronary heart disease (CHD) depending on the level of follicle-­stimulating hormone (FSH), testosterone (T), age and find if those parameters associated with anthropometric parameters, glycemia, insulinemia and HOMA-IR index, biomarkers of atherosclerosis. The study included 285 women aged 35–65 years (median age was 54.4 years (25% and 75% percentiles — 43.2 and 61.3 years, respectively) who had had myocardial infarction no earlier than 30 days before the examination. Patients were divided into the following age groups: 35–55 and 56–65 years (first and second age groups, respectively), and into groups according to the levels of sex hormones: FSH ≥ and <30 mIU/mL and testosterone ≥ and <3 nmol/L. Results of comparative and correlation analyzes demonstrates that in women 35–65 years old with FSH ≥30 mIU/mL, the levels of cathepsin D are higher (p<0.05) than in patients with FSH <30 mIU/mL, and in women 35–55 years old, the content of AP was also higher (p=0.025). Associations of a high level of androgen with lysosomal hyperenzymemia were demonstrated only in the second age group, where at a level of T ≥3 nmol/L, higher values of all three lysosomal enzymes were recorded. Multivariate analysis in both age groups is confirmed direct impact of periand postmenopausal periods on the levels of lysosomal enzymemia and, accordingly, a negative effect on the state of lysosomal membranes. Thus, FSH levels directly determined the concentrations of AP and cardiotropic cathepsin D. The levels of aDNAase in women with CHD of 56–65 years of age were positively correlated with indicators that determine insulin-­glucose homeostasis: glycemia (p<0.001), HOMA-IR index (p<0.001). Such associations of three marker lysosomal enzymes demonstrate the primary contribution of FSH ≥30 mIU/mL to an increase in the concentration of lysosomal hydrolases in women with CHD35–65 years old and the correlation of aDNAase with the processes triggered by insulin resistance.

1. BallabioA., Bonifacino J.S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol., 2020; 21 (2): 101–118. doi: 10.1038/s41580–019–0185–4

2. Hoes M.F., Tromp J., Ouwerkerk W., Bomer N., Oberdorf-¬Maass S.U., Samani N.J., Ng L.L., Lang C.C., van der Harst P., Hillege H., Anker S.D., Metra M., van Veldhuisen D.J., Voors A.A., van der Meer P. The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach. Eur. J. Heart Fail., 2020; 22 (11): 2102– 2111. doi: 10.1002/ejhf.1674

3. Rozenfeld P., Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol. Genet. Metab. 2017; 122 (3): 19–27. doi: 10.1016/j.ymgme.2017.09.004

4. Ahmad F., Leake D.S. Lysosomal oxidation of LDL alters lysosomal pH, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages. J. Lipid Res., 2019; 60 (1): 98–110. doi: 10.1194/jlr.M088245

5. Цыганкова О.В., Федорова Е.Л., Бондарева З.Г., Рагино Ю.И. Ишемическая болезнь сердца у женщин. Особенности факторов риска и клинического течения инфаркта миокарда в зависимости от возраста. Сердце: журнал для практикующих врачей, 2010; (1): 23–32.

6. Wei Y., Huang J. Role of estrogen and its receptors mediated-autophagy in cell fate and human diseases. J. Steroid Biochem. Mol. Biol., 2019; 191: 105380. doi: 10.1016/j.jsbmb.2019.105380

7. Azcoitia I., Barreto G.E., Garcia-Segura L.M. Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences. Front. Neuroendocrinol., 2019; 55: 100787. doi: 10.1016/j.yfrne.2019.100787

8. Цыганкова О.В., Николаев К.Ю., Федорова Е.Л., Бондарева З.Г., Рагино Ю.И., Платонов Д.Ю., Пустоветова М.Г. Факторы риска сердечно-сосудистых заболеваний. Взгляд на женщину. Атеросклероз, 2014; 10 (1): 44–55.

9. Цыганкова О.В., Николаев К.Ю., Федорова Е.Л., Бондарева З.Г. Обмен половых гормонов в организме мужчины через призму кардиоваскулярного риска. Атеросклероз и дислипидемии, 2014; (1): 17–24

10. Bartekova M., Radosinska J., Jelemensky M., Dhalla N.S. Role of cytokines and inflammation in heart function during health and disease. Heart Fail. Rev., 2018; 23 (5): 733–758. doi: 10.1007/s10741–018–9716-x

11. Puhl S.L., Steffens S. Neutrophils in postmyocardial infarction inflammation: Damage vs. resolution? Front. Cardiovasc. Med., 2019; 6: 1–25. doi: 10.3389/fcvm.2019.00025

12. Zhao D., Guallar E., Ouyang P., Subramanya V., Vaidya D., Ndumele C.E., Lima J.A., Allison M.A., Shah S.J., Bertoni A. G., Budoff M.J., Post W. S., Michos E. D. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J. Am. Coll. Cardiol., 2018; 71 (22): 2555–2566. doi: 10.1016/j.jacc.2018.01.083

13. Penn C.A., Chan J., Mesaros C., Snyder N.W., Rader D.J., Sammel M.D., Dokras A. Association of serum androgens and coronary artery calcium scores in women. Fertil. Steril., 2019; 112 (3): 586–593. doi: 10.1016/j.fertnstert.2019.04.024

14. Ng M. K., Quinn C.M., McCrohon J.A., Nakhla S., Jessup W., Handelsman D.J., Celermajer D. S., Death A. K. Androgens up-regulate atherosclerosis-¬related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis. J. Am. Coll. Cardiol., 2003; 42 (7): 1306–1313. doi: 10.1016/j.jacc.2003.07.002

15. Meun C., Franco O. H., Dhana K., Jaspers L., Muka T., Louwers Y., Ikram M.A., Fauser B.C.J.M., Kavousi M., Laven J. S.E. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: The Rotterdam Study. J. Clin. Endocrinol. Metab., 2018; 103 (4): 1622–1630. doi: 10.1210/jc.2017–02421

16. Цыганкова О.В., Платонов Д.Ю., Бондарева З.Г., Старичков А.А., Латынцева Л.Д. Ишемическая болезнь у женщин: патогенетические и патоморфологические особенности формирования и клинического течения. Проблемы женского здоровья, 2013; 8 (4): 50–59

17. Vivot K., Pasquier A., Goginashvili A., Ricci R. Breaking bad and breaking good: β-cell autophagy pathways in diabetes. J. Mol. Biol., 2020; 432 (5): 1494–1513. doi: 10.1016/j.jmb.2019.07.030

18. Sims-Robinson C., Bakeman A., Rosko A., Glasser R., Feldman E.L. The role of oxidized cholesterol in diabetes-induced lysosomal dysfunction in the brain. Mol. Neurobiol., 2016; 53 (4): 2287–2296. doi: 10.1007/s12035–015–9207–1