Centro Cardiologico Monzino, IRCCS, Milan, Italy.
Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
Biomed Pharmacother. 2022 Feb;146:112557. doi: 10.1016/j.biopha.2021.112557. Epub 2021 Dec 26.
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha-adrenergic receptor (α-ADR) overexpression found in BDNF mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF plasmid or exposed to pro-BDNF peptide. Finally, we show that homozygous BDNF CAD patients have hyper-reactive platelets overexpressing abundant α-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.
抑郁症与血栓形成风险和动脉事件有关，强烈建议在冠状动脉疾病（CAD）患者中进行适当的管理。我们之前已经表明，与抑郁症相关的脑源性神经营养因子（BDNF）Val66Met 多态性与小鼠的动脉血栓形成以及人类急性心肌梗死风险增加有关。在此基础上，我们扩展了先前关于 BDNFVal66Met 多态性的发现，表明去甲肾上腺素再摄取抑制剂去甲丙咪嗪可挽救行为障碍，降低动脉血栓形成风险，消除病理性凝血和血小板高反应性，使白细胞、血小板和骨髓巨核细胞数量正常化，并恢复同型敲入 BDNF Val66Met（BDNF）小鼠的生理去甲肾上腺素水平。体外数据证实了在 BDNF 小鼠中发现的增强的促凝活性和α-肾上腺素能受体（α-ADR）过表达，并提供了证据表明，在存在 Met 变体的情况下，去甲肾上腺素对于上调促凝活性和增强血小板生成至关重要。α-ADR 拮抗剂 rauwolscine 可挽救 BDNF 小鼠的促血栓形成表型，并降低转染 BDNF 质粒或暴露于前 BDNF 肽的细胞中的促凝活性和血小板生成。最后，我们表明，同型 BDNF CAD 患者的血小板过度表达丰富的α-ADR，表现出高反应性。与 BDNF 患者相比，其巨核细胞中大量前血小板的释放很好地反映了他们更高的循环血小板数量。这些数据揭示了 Met 等位基因在去甲肾上腺素/α-ADR 途径失调中的前所未有的作用，这可能解释了其易发生动脉血栓形成的倾向。总体而言，开发α-ADR 抑制剂可能代表针对该特定 CAD 患者亚组中与抑郁症相关的血栓形成疾病的药理学治疗方法。
