BDNF/TrkB signaling in stable coronary artery disease

Aim. To study the serum content of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) in patients with coronary artery disease (CAD) and evaluate the relationship of BDNF/TrkB signaling with the severity of coronary atherosclerosis, systemic inflammation (IL-2, IL-4, IL-6, IL-10, TNF-α) and angiogenesis (VEGF).

Material and methods. The study included 99 patients with stable CAD who underwent coronary angiography and 30 healthy volunteers. Coronary atherosclerosis was assessed using the Gensini score (GS). In blood serum, the concentrations of BDNF, TrkB, VEGF, IL-2, IL-4, IL-6, IL-10, TNF-α were determined using the enzyme immunoassay. Cluster, correlation, and regression analyzes were used.

Results. In patients with CAD, a wide range of variations in BDNF concentrations was observed. To determine homogeneous groups using the k-means clustering, three clusters with different BDNF/TrkB axis vectors were identified. Patients differed in the severity of coronary atherosclerosis, the manifestation of the inflammatory reaction, and the intensity of angiogenesis. In patients with initial and moderate atherosclerotic changes in the coronary arteries, a normal concentration of BDNF and an increased level of TrkB (22,35/1,18 ng/ml) were noted. In patients with severe coronary atherosclerosis, two different BDNF/TrkB variants have been identified. Decreased BDNF and increased TrkB (6,0/1,52 ng/ml) were associated with low VEGF and increased IL-6. Elevated BDNF and normal TrkB values (26,95/0,96 ng/ml) were characteristic of patients with high VEGF expression, indicating angiogenesis activation and/or vulnerable plaques. A direct relationship between BDNF and VEGF (r=0,536, p<0,001) and an inverse relationship with TrkB (r=-0,301, p=0,019), IL-6 (r=-0,306, p=0,002) was revealed. TrkB levels were correlated with TNF-α (r=0,403, p=0,001). Regression analysis showed that BDNF expression is influenced by TrkB (β=-0,237, p=0,009), VEGF (β=0,490, p<0,001), IL-6 (β=-0,339, p<0,001).

Conclusion. In patients with stable CAD, different levels of BDNF/TrkB expression were found, which were associated with coronary atherosclerosis severity. BDNF/TrkB signaling is involved in the regulation of inflammation and angiogenesis in stable CAD.

1. Milutinović A, Šuput D, Zorc-Pleskovič R.Pathogenesis of atherosclerosis in the tunica intima, media, and adventitia of coronary arteries: An updated review. Bosn J Basic Med Sci. 2020;20(1):21-30. doi:10.17305/bjbms.2019.4320.

2. Pius-Sadowska E, Machaliński B. BDNF-A key player in cardiovascular system. J Mol Cell Cardiol. 2017;110:54-60. doi:10.1016/j.yjmcc.2017.07.007.

3. Mori A, Nishioka Y, Yamada M, et al. Brain-derived neurotrophic factor induces angiogenin secretion and nuclear translocation in human umbilical vein endothelial cells. Pathol Res Pract. 2018;214:521-6. doi:10.1016/j.prp.2018.02.013.

4. Usui T, Naruo A, Okada M, et al. Brain-derived neurotrophic factor promotes angiogenic tube formation through generation of oxidative stress in human vascular endothelial cells. Acta Physiol (Oxf). 2014;211(2):385-94. doi:10.1111/apha.12249.

5. Kytikova OY, Novgorodtseva TP, Denisenko YK, et al. Brain-derived neurotrophic factor and coronary artery disease. Russian Open Medical Journal. 2022;11(2):e0202. (In Russ.) doi:10.15275/rusomj.2022.0202.

6. Amadio P, Cosentino N, Eligini S, et al. Potential Relation between Plasma BDNF Levels and Human Coronary Plaque Morphology. Diagnostics (Basel). 2021;11(6):1010. doi:10.3390/diagnostics11061010.

7. Sustar A, Perkovic MN, Erjavec GN, et al. Association between reduced brain-derived neurotrophic factor concentration & coronary heart disease. Indian J Med Res. 2019;150(1):43-9. doi:10.4103/ijmr.IJMR_1566_17.

8. Kaess BM, Preis SR, Lieb W, et al. Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community. J Am Heart Assoc. 2015;4(3):e001544. doi:10.1161/JAHA.114.001544.

9. Xia F, Zeng Q, Chen J.Circulating brain-derived neurotrophic factor dysregulation and its linkage with lipid level, stenosis degree, and inflammatory cytokines in coronary heart disease. J Clin Lab Anal. 2022;36:e24546. doi:10.1002/jcla.24546.

10. Shvaikovskaya AA, Zhanaeva SY, Evsyukova AV, et al. Brain neurotrophic factor (BDNF) and its diagnostic significance when measured in blood: analytical review. Yakut Medical Journal. 2020;3(71):105-10. (In Russ.) doi:10.25789/YMJ.2020.71.27.

11. Ribeiro D, Petrigna L, Pereira FC, et al. The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review. Int J Mol Sci. 2021;22(16):8814. doi:10.3390/ijms22168814.

12. Jiang H, Huang S, Li X, et al. Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE-/-mice. Oncotarget. 2015;6(31):30640-9. doi:10.18632/oncotarget.5855.

13. Tschorn M, Kuhlmann SL, Rieckmann N, et al. Brain-derived neurotrophic factor, depressive symptoms and somatic comorbidity in patients with coronary heart disease. Acta Neuropsychiatr. 2021;33(1):22-30. doi:10.1017/neu.2020.31.

14. Huang A, Qi X, Cui Y, et al. Serum VEGF: Diagnostic Value of Acute Coronary Syndrome from Stable Angina Pectoris and Prognostic Value of Coronary Artery Disease. Cardiol Res Pract. 2020;2020:6786302. doi:10.1155/2020/6786302.

15. Atamas OV, Antonyuk МV. Сytokine profile in patients with obstructive coronary artery disease. The Siberian Journal of Clinical and Experimental Medicine. 2023;38(2):114-21. (In Russ.) doi:10.29001/2073-8552-2023-38-2-114-121.