The α 2 -adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism

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.