Association of sex and age with the ceramide profile of adipose tissue in patients with coronary artery disease

Background. Coronary artery disease (CAD) is associated with complex molecular changes in adipose tissue (AT) that go beyond simple energy storage. Current studies indicate the active participation of AT in metabolic regulation and secretion of bioactive lipid mediators, including ceramides, the role of which in CAD pathogenesis remains poorly understood, particularly with regard to age and sex differences.

Aim. To characterize the ceramide profile in subcutaneous, epicardial and perivascular AT (SAT, EAT, PVAT) in patients with CAD, with regard to age and sex differences.

Materials and Methods. A lipidomic study of the ceramide profile was conducted in SAT, EAT, PVAT samples obtained from 58 patients with CAD who underwent coronary artery bypass grafting (single-center prospective clinical study). The ceramide composition was analyzed by high-performance liquid chromatography with tandem mass spectrometric detection.

Results. Ageand sex-related differences in the AT ceramide profile were identified. In men, the concentrations of cardionegative ceramides (Cer d18:1/14:0, Cer d18:1/18:0, Cer d18:1/20:0, Cer d18:1/22:0) and Cer d18:1/24:1 were higher (p < 0.05). In PVAT of men, the levels of Cer 14:0, 16:0 and 22:4 were increased (p < 0.001). In EAT and PVAT of women, increased levels of Cer 18:0 and 23:0 were noted (p < 0.05). In EAT and PAT of women, the concentrations of Cer 20:0, 22:0 and 24:1 were higher (p < 0.05). The highest levels of cardionegative ceramides were observed in PVAT of patients aged over 75 years. The ratio of cardionegative to cardioprotective ceramides was higher in EAT in individuals aged 60–74 years and in PVAT in those aged over 75 years.

Conclusion. Significant sexand age-related differences in the AT ceramide profile of patients with CAD were identified, emphasizing the need to consider these factors when assessing cardiovascular risk. The data obtained may contribute to the development of new therapeutic strategies aimed at modulating the ceramide profile of AT to reduce cardiovascular risk.

1. Noothi SK, Ahmed MR, Agrawal DK. Residual risks and evolving atherosclerotic plaques. Mol Cell Biochem. 2023; 478(12): 2629-2643. doi: 10.1007/s11010-023-04689-0

2. St Sauver JL, LeBrasseur NK, Rocca WA, Olson JE, Bielinski SJ, Sohn S, et al. Cohort study examining associations between ceramide levels and risk of multimorbidity among persons participating in the Mayo Clinic Biobank. BMJ Open. 2023; 13(4): e069375. doi: 10.1136/bmjopen-2022-069375

3. Poss AM, Summers SA. Too much of a good thing? An evolutionary theory to explain the role of ceramides in nafld. Front Endocrinol. 2020; 11: 505. doi: 10.3389/fendo.2020.00505

4. Brel NK, Gruzdeva OV, Kokov AN, Masenko VL, et al. Relationship of coronary calcinosis and local fat deposts in patients with coronary artery disease. Complex Issues of Cardiovascular Diseases. 2022; 11(3): 51-63 (In Russ.). doi: 10.17802/2306-1278-2022-11-3-51-63

5. Belik EV, Dyleva YA, Uchasova EG, Poddubnyak AO, Sotnikov AV, Gorbatovskaya EE, et al. Effect of smoking on the ceramide profile of adipose tissue in patients with cardiovascular diseases. Russian Journal of Cardiology. 2024; 29(11): 107-113. (In Russ.). doi: 10.15829/1560-4071-2024-5998

6. Blachnio-Zabielska AU, Koutsari Ch, Tchkonia T, Jensen MD. Sphingolipid content in human adipose tissue: relationship with adiponectin and insulin resistance. Obesity. 2012; 20(12): 2341-7. doi: 10.1038/oby.2012.126

7. Brusatori M, Wood MH, Tucker SC, Maddipati KR, Koya K, Auner GW, et. al. Ceramide changes in abdominal subcutaneous and visceral adipose tissue among diabetic and nondiabetic patients. J Diabetes. 2022; 14(4): 271-281. doi: 10.1111/1753-0407.13262

8. Gavin KM, Bessesen DH. Sex Differences in Adipose Tissue Function. Endocrinol Metab Clin North Am. 2020; 49(2): 215-228. doi: 10.1016/j.ecl.2020.02.008

9. Li WH. Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes. Molecules. 2022; 27(18): 6117. doi: 10.3390/molecules27186117

10. Nicholson RJ, Norris MK, Poss AM, Holland WL, Summers SA. The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease. Annual review of nutrition. 2022; 42: 115-144. doi: 10.1146/annurev-nutr-062220-112920

11. Kokov AN, Brel NK, Masenko VL, Gruzdeva OV, Karetnikova VN, Kashtalap VV, et al. Quantitative assessment of visceral adipose depot in patients with ischemic heart disease by using of modern tomographic methods. Complex Issues of Cardiovascular Diseases. 2017; 6(3): 113-119. (In Russ.). doi: 10.17802/2306-1278-2017-6-3-113-119

12. Meroni SB, Pellizzari EH, Cánepa DF, Cigorraga SB. Possible involvement of ceramide in the regulation of rat Leydig cell function. J Steroid Biochem Mol Biol. 2000; 75(45): 307-13. doi: 10.1016/s0960-0760(00)00188-6

13. Wang D, Tang Y, Wang Z. Role of sphingolipid metabolites in the homeostasis of steroid hormones and the maintenance of testicular functions. Front Endocrinol. 2023; 14: 1170023. doi: 10.3389/fendo.2023.1170023

14. Fretts AM, Jensen PN, Hoofnagle AN, McKnight B, Sitlani CM, Siscovick DS, et al. Circulating Ceramides and Sphingomyelins and Risk of Mortality: The Cardiovascular Health Study. Clin. Chem. 2021; 67: 1650-1659. doi:10.1093/clinchem/hvab182

15. Kim KI. Risk Stratification of Cardiovascular Disease according to Age Groups in New Prevention Guidelines: A Review. J Lipid Atheroscler. 2023; 12(2): 96-105. doi: 10.12997/jla.2023.12.2.96

16. Rodgers JL, Jones J, Bolleddu SI, Vanthenapalli S, Rodgers LE, Shah K, et al. Cardiovascular Risks Associated with Gender and Aging. J Cardiovasc Dev Dis. 2019; 6(2): 19. doi: 10.3390/jcdd6020019

17. Ho QWC, Zheng X, Ali Y. Ceramide Acyl Chain Length and Its Relevance to Intracellular Lipid Regulation. Int J Mol Sci. 2022; 23(17): 9697. doi: 10.3390/ijms23179697

18. Gruzdeva O, Dyleva Y, Belik E, Uchasova E, Ponasenko A, Ivanov S, et al. Expression of Ceramide-Metabolizing Enzymes in the Heart Adipose Tissue of Cardiovascular Disease Patients. Int J Mol Sci. 2023; 24: 9494. doi: 10.3390/ijms24119494

19. Bonzón-Kulichenko E, Moltó E, Pintado C, Fernández A, Arribas С, Schwudke D, et al. Changes in Visceral Adipose Tissue Plasma Membrane Lipid Composition in Old Rats Are Associated with Adipocyte Hypertrophy with Aging. J Gerontol a Biol Sci Med Sci. 2018; 73(9): 1139-1146. doi: 10.1093/gerona/gly081

20. Pamplona R. Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta. 2008; 1777(10): 1249-1262. doi: 10.1016/j.bbabio.2008.07.003

21. Laaksonen R, Ekroos K, Sysi-Aho M, Hilvo M, Vihervaara T, Kauhanen D, et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. Eur Heart J. 2016; 37(25): 1967-1976. doi: 10.1093/eurheartj/ehw148

22. Akawi N, Checa A, Antonopoulos AS, Akoumianakis I, Daskalaki E, Kotanidis CP, et al. Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients with Cardiovascular Disease. J Am Coll Cardiol. 2021; 77(20): 2494-2513. doi: 10.1016/j.jacc.2021.03.314

23. Obas V, Vasan RS. The aging heart. Clin Sci (Lond). 2018; 132(13): 1367-1382. doi: 10.1042/CS20171156