EXPRESSION OF ADIPONECTIN AND ITS RECEPTORS IN ADIPOSE TISSUE OF EPICARDIAL AND PERICORONARY LOCALIZATION OF PATIENTS WITH CARDIOVASCULAR DISEASES

Aim. To evaluate the expression features of total adiponectin (ADPN), high-molecular-weight adiponectin (HMW-ADPN) and its receptors in epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) of patients with cardiovascular diseases (CVD).

Materials and methods. The study included 156 patients with stable coronary artery disease and 120 patients with degenerative non-rheumatic valvular heart disease. Patients in the study groups were matched for gender, age, and body mass index. During surgery, 3-5 g samples of subcutaneous, epicardial, and pericoronary AT (SAT, EAT, and PCAT) were obtained. Adiponectin gene expression (ADIPOQ) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Total ADPN, HMW-ADPN, and ADPN receptor concentrations were determined by enzyme immunoassay according to the manufacturers' protocols. Statistical analysis was performed using GraphPad Prism 8 and Statistica 12.0.

Results. Patients with coronary atherosclerosis had low ADIPOQ mRNA levels, low total ADPN and AdipoR1 receptor levels in EAT adipocyte cultures compared to SAT adipocytes and the acquired heart defects (AHD) group. The levels of HMW-ADPN and AdipoR2 were minimal in both EAT and PCAT adipocyte cultures, which were higher among individuals with ADP. Severe and extremely severe coronary artery disease was associated with low ADIPOQ mRNA expression and low HMW-ADPN levels in EAT and PCAT and AdipoR2 deficiency in EAT.

Conclusion. Coronary atherosclerosis is characterized by the presence of HMW-ADPN and ADPN receptor deficiency not only in EAT adipocytes but also in PCAT adipocytes. A decrease in the level of HMW-ADPN secretion in adipocytes of EAT and PCAT and the expression of AdipoR2 in EAT is associated with more severe coronary artery disease.

1. References

2. Guerre-Millo M. Adiponectin: an update. Diabetes Metab. 2008;34(1):12–8. doi: 10.1016/j.diabet.2007.08.002

3. Pandey G.K., Vadivel S., Raghavan S., Mohan V., Balasubramanyam M., Gokulakrishnan K. High molecular weight adiponectin reduces glucolipotoxicity-induced inflammation and improves lipid metabolism and insulin sensitivity via APPL1-AMPK-GLUT4 regulation in 3T3-L1 adipocytes. Atherosclerosis. 2019; 288:67-75. doi: 10.1016/j.atherosclerosis.2019.07.011

4. Khoramipour K., Chamari K., Hekmatikar A., Ziyaiyan A., Taherkhani S., Elguindy N., Bragazzi N. Adiponectin: Structure, Physiological Functions, Role in Diseases, and Effects of Nutrition. Nutrients. 2021; 13:1180. doi: 10.3390/nu13041180

5. [Davydova V., Nikiforov V., Khalimov Yu. Sh. The role of adipokines and epicardial adipose tissue thickness in predicting outcomes of acute coronary syndrome. Therapy. 2023; 4: 38-46. (In Russ)]

6. Pischon T., Girman C.J., Hotamisligil G.S., Rifai N., Hu F.B., Rimm E.B. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291(14):1730–1737. doi: 10.1001/jama.291.14.1730

7. Liberale L., Bonaventura A., Vecchiè A., Matteo C., Dallegri F., Montecucco F., Carbone F. The Role of Adipocytokines in Coronary Atherosclerosis. Curr. Atheroscler. Rep. 2017; 19:10. doi: 10.1007/s11883-017-0657-y

8. Au Yeung S.L., Schooling C.M. Adiponectin and coronary artery disease risk: a bi-directional Mendelian randomization study. Int J Cardiol. 2018; 268:222-226. doi: 10.1016/j.ijcard.2018.03.132

9. Zhang Y. Q., Zhang Y. W., Dai J. L., Li C., Wang W. Q., Zhang H. F., Lau W. B., Wang X. M., Liu X. G. & Li R. Serum CTRP9 and high-molecular weight adiponectin are associated with ischemic stroke. BMC Neurol. 2022;22(1):429. doi: 10.1186/s12883-022-02967-w

10. Kalisz M., Baranowska B., Wolinska-witort E., Maczewski M., Mackiewicz U., Tulacz D., Gora M., Martynska L., Bik W. Total and high molecular weight adiponectin levels in the rat model of post-myocardial heart failure. J Physiol Pharmacol. 2015;66(5):673-680.

11. Pischon T., Hu F.B., Girman C.J., Rifai N., Manson J.E., Rexrode K.M., Rimm E.B. Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women. Atherosclerosis. 2011; 219(1): 322–329. doi: 10.1016/j.atherosclerosis.2011.07.011

12. Gruzdeva O.V., Dyleva Y.A., Belik E.V., Sinitsky M.Y., Stasev A.N., Kokov A.N., Brel N.K., Krivkina E.O., Bychkova E.E., Tarasov R.S., et al. Relationship between Epicardial and Coronary Adipose Tissue and the Expression of Adiponectin, Leptin, and Interleukin 6 in Patients with Coronary Artery Disease. J. Pers. Med. 2022; 12: 129. doi:10.3390/jpm12020129

13. Lara-Castro C., Luo N., Wallace P., et al. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes. 2006; 55:249-259. doi:10.2337/diabetes.55.01.06.db05-1105

14. Ma Y., Liu D. Hydrodynamic delivery of adiponectin and adiponectin receptor 2 gene blocks high-fat diet-induced obesity and insulin resistance. Gene Ther. 2013;20(8):846-852. doi:10.1038/gt.2013.8

15. Liu Y., Palanivel R., Rai E., et al. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes. 2015;64(1):36-48. doi: 10.2337/db14-0267

16. von Eynatten M., Humpert P.M., Bluemm A., Lepper P.M., Hamann A., Allolio B., Nawroth P.P., Bierhaus A., Dugi K.A. High-molecular weight adiponectin is independently associated with the extent of coronary artery disease in men. Atherosclerosis. 2008;199(1):123-8. doi: 10.1016/j.atherosclerosis.2007.10.002

17. Sahasrabuddhe A.V., Pitale S.U., Sivanesan S.D., Deshpande P.K., Deshpande S.P., Daiwile A. Pathogenic gene expression of epicardial adipose tissue in patients with coronary artery disease. Indian J Med Res. 2020;151(6):554–561. doi: 10.4103/ijmr.IJMR_1374_18

18. Zhou Y., Wei Y., Wang L., Wang X., Du X., Sun Z., Dong N., Chen X. Decreased adiponectin and increased inflammation expression in epicardial adipose tissue in coronary artery disease. Cardiovasc Diabetol. 2011; 10:2. doi: 10.1186/1475-2840-10-10-2

19. Rahmani A., Toloueitabar Y., Mohsenzadeh Y., Hemmati R., Sayehmiri K., Asadollahi K. Association between plasma leptin/adiponectin ratios with the extent and severity of coronary artery disease. BMC Cardiovascular Disorders. 2020; 20:474. doi: 10.1186/s12872-020-01723-7

20. [Gruzdeva O.V., Dyleva Yu.A., Belik E.V., Akbasheva O.E., Borodkina D.A., Sinitsky M.Yu., Naumov D.Yu., Bychkova E.E., Fanaskova E.V., Palicheva E.I., Kuzmina A.A., Barbarash O.L. Expression of adipocytokines in cardiac fat depots depending on the degree of coronary artery atherosclerosis in patients with coronary artery disease. Vestnik RAMS.2021;76(2):159–168. (In Russ)]

21. Kobayashi H., Ouchi N., Kihara S., Walsh K., Kumada M., Abe Y., Funahashi T., Matsuzawa Y. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res. 2004; 94: e27-e31. doi: 10.1161/01.RES.0000119921.86460.37

22. Cai X., Li X., Li L., Huang X.Z., Liu Y.S., Chen L., Zhang K., Wang L., Li X., Song J., et al. Adiponectin reduces carotid atherosclerotic plaque formation in ApoE−/− mice: Roles of oxidative and nitrosative stress and inducible nitric oxide synthase. Mol. Med. Rep. 2015; 11:1715–1721. doi: 10.3892/mmr.2014.2947

23. Yamauchi T., Nio Y., Maki T., Kobayashi M., Takazawa T., Iwabu M., Okada-Iwabu M., Kawamoto S., Kubota N., Kubota T., et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 2007; 13:332–339. doi: 10.1038/nm1557

24. Holland W.L., Xia J.Y., Johnson J.A., Sun K., Pearson M.J., Sharma A.X., Quittner-Strom E., Tippetts T.S., Gordillo R., Scherer P.E. Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis. Mol. Metab. 2017; 6:267–275. doi: 10.1016/j.molmet.2017.01.002

25. [Gruzdeva O. V., Akbasheva O. E., Dyleva Yu. A., Antonova L. V., Matveeva V. G., Uchasova E. G., Fanaskova E. V., Karetnikova V. N., Ivanov S. V., Barbarash O. L. Profiles of adipokines and cytokines of epicardial and subcutaneous adipose tissue in patients with coronary heart disease. Bulletin of Experimental Biology and Medicine. 2017; 163:608–611. (In Russ)]

26. Kim J.Y., van de Wall E., Laplante M., et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007; 117:2621-2637. doi: 10.1172/JCI31021