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The α 2 -adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism.
- Source :
-
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Feb; Vol. 146, pp. 112557. Date of Electronic Publication: 2021 Dec 26. - Publication Year :
- 2022
-
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 (BDNF <superscript>Met/Met</superscript> ) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha <subscript>2A</subscript> -adrenergic receptor (α <subscript>2A</subscript> -ADR) overexpression found in BDNF <superscript>Met/Met</superscript> 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 <subscript>2</subscript> -ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF <superscript>Met/Met</superscript> mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF <superscript>Met</superscript> plasmid or exposed to pro-BDNF <superscript>Met</superscript> peptide. Finally, we show that homozygous BDNF <superscript>Met/Met</superscript> CAD patients have hyper-reactive platelets overexpressing abundant α <subscript>2A</subscript> -ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF <superscript>Val/Val</superscript> patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α <subscript>2A</subscript> -ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α <subscript>2A</subscript> -ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.<br /> (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Aged
Aged, 80 and over
Animals
Coronary Artery Disease pathology
Desipramine pharmacology
Female
Humans
Male
Mice
Middle Aged
Polymorphism, Single Nucleotide
Blood Coagulation physiology
Brain-Derived Neurotrophic Factor genetics
Depression pathology
Norepinephrine metabolism
Receptors, Adrenergic, alpha-2 metabolism
Thrombosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1950-6007
- Volume :
- 146
- Database :
- MEDLINE
- Journal :
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
- Publication Type :
- Academic Journal
- Accession number :
- 34965503
- Full Text :
- https://doi.org/10.1016/j.biopha.2021.112557