Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.
Int J Mol Sci. 2018 Oct 19;19(10):3235. doi: 10.3390/ijms19103235.
Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been associated with increased susceptibility to develop mood disorders and recently it has been also linked with cardiovascular disease (CVD). Interestingly, stressful conditions unveil the anxious/depressive-like behavioral phenotype in heterozygous BDNFVal66Met (BDNF) mice, suggesting an important relationship in terms of gene-environment interaction (GxE). However, the interplay between stress and BDNF in relation to CVD is completely unknown. Here, we showed that BDNF mice display a greater propensity to arterial thrombosis than wild type BDNF mice after 7 days of restraint stress (RS). RS markedly increased the number of leukocytes and platelets, and induced hyper-responsive platelets as showed by increased circulating platelet/leukocyte aggregates and enhanced expression of P-selectin and GPIIbIIIa in heterozygous mutant mice. In addition, stressed BDNF mice had a greater number of large and reticulated platelets but comparable number and maturation profile of bone marrow megakaryocytes compared to BDNF mice. Interestingly, RS led to a significant reduction of BDNF expression accompanied by an increased activity of tissue factor in the aorta of both BDNF and BDNF mice. In conclusion, we provide evidence that sub-chronic stress unveils prothrombotic phenotype in heterozygous BDNF Val66Met mice affecting both the number and functionality of blood circulating cells, and the expression of key thrombotic molecules in aorta. Human studies will be crucial to understand whether this GxE interaction need to be taken into account in risk stratification of coronary artery disease (CAD) patients.
脑源性神经营养因子（BDNF）Val66Met 多态性与易患心境障碍有关，最近也与心血管疾病（CVD）有关。有趣的是，在杂合子 BDNFVal66Met（BDNF）小鼠中，应激条件揭示了焦虑/抑郁样行为表型，这表明在基因-环境相互作用（GxE）方面存在重要关系。然而，应激和 BDNF 与 CVD 之间的相互作用尚完全未知。在这里，我们表明，BDNF 小鼠在 7 天的束缚应激（RS）后比野生型 BDNF 小鼠更容易发生动脉血栓形成。RS 显著增加了白细胞和血小板的数量，并诱导了高反应性血小板，表现为循环血小板/白细胞聚集体增加，以及杂合突变小鼠中 P-选择素和 GPIIbIIIa 的表达增强。此外，与 BDNF 小鼠相比，应激 BDNF 小鼠的大血小板和网织血小板数量更多，但骨髓巨核细胞的数量和成熟谱相似。有趣的是，RS 导致 BDNF 表达显著减少，同时在 BDNF 和 BDNF 小鼠的主动脉中组织因子活性增加。总之，我们提供的证据表明，亚慢性应激会揭示杂合子 BDNF Val66Met 小鼠的促血栓形成表型，影响循环血细胞的数量和功能，以及主动脉中关键血栓形成分子的表达。人类研究对于理解这种 GxE 相互作用是否需要在冠心病（CAD）患者的风险分层中考虑至关重要。
