Abstract:
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 (BDNFMet/Met) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha2A-adrenergic receptor (α2A-ADR) overexpression found in BDNFMet/Met 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 α2-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNFMet/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNFMet plasmid or exposed to pro-BDNFMet peptide. Finally, we show that homozygous BDNFMet/Met CAD patients have hyper-reactive platelets overexpressing abundant α2A-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNFVal/Val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α2A-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α2A-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.
摘要:
抑郁症与血栓形成风险和动脉事件有关,强烈建议在冠心病(CAD)患者中进行正确的治疗.我们以前已经证明脑源性神经营养因子(BDNF)Val66Met多态性,与抑郁症有关,与小鼠动脉血栓形成有关,并增加人类急性心肌梗塞的风险。在这里,扩展了之前关于BDNFVal66Met多态性的发现,我们证明了地昔帕明,去甲肾上腺素再摄取抑制剂,拯救行为障碍,降低动脉血栓形成的风险,消除病理性凝血和血小板高反应性,使白细胞正常化,血小板,纯合敲入BDNFVal66Met(BDNFMet/Met)小鼠的骨髓巨核细胞数量和恢复生理去甲肾上腺素水平。体外数据证实了在BDNFMet/Met小鼠中发现的增强的促凝血活性和α2A-肾上腺素能受体(α2A-ADR)过表达,在存在Met变体的情况下,去甲肾上腺素对于上调促凝血活性和增强血小板生成至关重要。α2-ADR拮抗剂rauwolscine挽救BDNFMet/Met小鼠的血栓前表型,并降低用BDNFMet质粒转染或暴露于前BDNFMet肽的细胞中的促凝血活性和血小板生成。最后,我们显示纯合BDNFMet/MetCAD患者具有高反应性血小板过表达丰富的α2A-ADR。与BDNFVal/Val患者相比,其巨核细胞的大量前血小板释放很好地反映了其较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/α2A-ADR通路失调中前所未有的作用,这可能解释了动脉血栓形成的易感性。总的来说,在这一特定的CAD患者亚组中,α2A-ADR抑制剂的开发可能代表了抑郁症相关血栓性疾病的药物治疗.