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The α2-adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with

Leonardo Sandrini1, Patrizia Amadio1, Alessandro Ieraci2

  • 1Centro Cardiologico Monzino, IRCCS, Milan, Italy.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|December 29, 2021
PubMed

Insights

Depression increases thrombotic risk in coronary artery disease (CAD) patients. The Brain-Derived Neurotrophic Factor (BDNF)Met allele dysregulates norepinephrine/α2A-ADR, leading to arterial thrombosis, but α2A-ADR inhibitors may offer treatment.

Area of Science:

  • Cardiovascular Medicine
  • Neuroscience
  • Genetics

Background:

  • Depression is linked to increased thrombotic risk and arterial events, particularly in coronary artery disease (CAD) patients.
  • The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism is associated with depression and has been linked to arterial thrombosis and myocardial infarction risk.
  • Previous research indicated a connection between the BDNF Val66Met polymorphism and arterial thrombosis.

Purpose of the Study:

  • To investigate the role of the BDNF Val66Met polymorphism in arterial thrombosis and coagulation.
  • To explore the therapeutic potential of desipramine and α2A-adrenergic receptor (α2A-ADR) antagonists in mitigating thrombosis associated with the BDNF Met allele.
  • To elucidate the mechanism by which the BDNF Met allele influences norepinephrine signaling and platelet activity.

Main Methods:

  • Utilized homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice to study behavioral and thrombotic phenotypes.
  • Administered desipramine (a norepinephrine reuptake inhibitor) and rauwolscine (an α2-ADR antagonist) to assess their effects on thrombosis and coagulation.
  • Conducted in vitro experiments using cells transfected with BDNFMet plasmid or exposed to pro-BDNFMet peptide to confirm enhanced procoagulant activity and α2A-ADR overexpression.
  • Analyzed platelet reactivity, coagulation, norepinephrine levels, and megakaryocyte function in both animal models and human CAD patients with different BDNF genotypes.

Main Results:

  • Desipramine treatment rescued behavioral impairments, reduced arterial thrombosis risk, normalized coagulation, and restored norepinephrine levels in BDNFMet/Met mice.
  • In vitro studies confirmed enhanced procoagulant activity and α2A-ADR overexpression in the presence of the BDNF Met variant, with norepinephrine crucial for up-regulating procoagulant activity and platelet generation.
  • Rauwolscine effectively rescued the prothrombotic phenotype in BDNFMet/Met mice and reduced procoagulant activity and platelet generation in cellular models.
  • Homozygous BDNFMet/Met CAD patients exhibited hyper-reactive platelets with α2A-ADR overexpression and increased proplatelet release from megakaryocytes, leading to higher circulating platelet counts compared to BDNFVal/Val patients.

Conclusions:

  • The BDNF Met allele plays a significant role in dysregulating the norepinephrine/α2A-ADR pathway, contributing to arterial thrombosis predisposition.
  • The findings reveal an uncharacterized mechanism linking the BDNF Met allele to increased thrombotic risk via norepinephrine and α2A-ADR signaling.
  • α2A-ADR inhibitors represent a potential therapeutic strategy for managing depression-associated thrombotic conditions in CAD patients carrying the BDNF Met allele.

Keywords:
Anxiety/depressionBDNF Val66Met polymorphismPlateletsProcoagulant activityThrombosisα(2)-adrenergic receptor

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