VPB0518 - Disentangle the relationship between depression and arterial thrombosis associated with BDNFVal66Met polymorphism: the role of α 2-adrenergic receptor pathway

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

Leonardo Sandrini, PhD

Post-Doc Fellow
Centro Cardiologico Monzino IRCCS
Milan, Lombardia, Italy

Co-Author(s)

PA

Patrizia Amadio

Senior Scientist at the Heart and Brain Axis Unit
Centro Cardiologico Monzino IRCCS
Milan, Lombardia, Italy
AI

Alessandro Ieraci

Researcher Assistant Professor at Department of Pharmaceutical Sciences
Università degli Studi di Milano
Milan, Lombardia, Italy
MA

Malara Alessandro

Researcher
Department of Molecular Medicine, University of Pavia and IRCCS San Matteo Foundation
Pavia, Lombardia, Italy
JW

José Pablo Werba

Head of the
Atherosclerosis research and prevention Unit, Centro Cardiologico Monzino, IRCCS
Milano, Lombardia, Italy
PS

Paolo Maria Soprano

Researcher
Department of Molecular Medicine, University of Pavia and IRCCS San Matteo Foundation
Pavia, Lombardia, Italy
Alessandra Balduini, MD

MD, PhD
University of Pavia, Pavia, Italy
Pavía, Lombardia, Italy
MZ

Marta Zarà

Researcher at the Brain-Heart Axis Unit
Centro Cardiologico Monzino IRCCS
Milan, Lombardia, Italy
AB

Alice Bonomi

biostatistician
Centro Cardiologico Monzino IRCCS
Milano, Lombardia, Italy
FV

Fabrizio Veglia

Researcher
Biostatistics Unit, Centro Cardiologico Monzino, IRCCS
Milano, Lombardia, Italy
GC

Gualtiero Ivanhoe Colombo

Researcher
Immunology and Functional Genomic Unit, Centro Cardiologico Monzino, IRCCS
Milano, Lombardia, Italy
MP

Maurizio Popoli

Professor
Department of Pharmaceutical Sciences, Università degli Studi di Milano
Milano, Lombardia, Italy
FL

Francis S Lee

MD
Department of Psychiatry, Weill Cornell Medical College
New York, New York, United States
ET

Elena Tremoli

Scientific director
Maria Cecilia Hospital
Cotignola, Toscana, Italy
Silvia Stella Barbieri, PhD

Head of the Brain-Heart Axis Unit
Centro Cardiologico Monzino IRCCS
Milan, Lombardia, Italy

Background: Depression represents an independent risk factor for cardiovascular diseases, but the beneficial effects of antidepressants in patients with concomitant depression and cardiovascular events are still under debate. 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. Interestingly, BDNFMet/Met mice, as well as CAD patients, have hyper-reactive platelets overexpressing α2A-adrenergic receptor (α2A-ADR), providing that this mouse model is a good tool to study novel strategies for these pathologies.

Aims: To investigate the implication of α2-ADR pathway in depression and arterial thrombosis associated with BDNFVal66Met polymorphism.

Methods: Rauwolscine or desipramine were administered to wild-type and BDNFMet/Met mice. Behaviour and carotid artery thrombosis were assessed by novelty-suppressed feeding and FeCl3 model, respectively. Mouse platelets activation profile was characterized by flow cytometry. To examine the effect of mutation per see, in vitro experiments were performed in Hela and Ea.hy926 cells, and megakaryocytes, differentiated from peripheral blood CD34+ and CD45+ cells of healthy subjects, treated with ProBDNFVal and ProBDNFMet cleavable peptide; and in Hela cells transfected with BDNFVal (HelaVal) and BDNFMet (HelaMet) plasmids.

Results: HelaMet cells as well as both cell types and megakaryocytes treated with proBDNFMet-peptide displayed a higher susceptibility to thrombosis and norepinephrine was crucial to up-regulate procoagulant activity and enhance platelet generation. Rauwolscine, a α2-ADR antagonist, decreased in vitro all the effects related to Met mutation, and in vivo abolished platelet hyper-reactivity, reduced vascular procoagulant activity, normalized leukocyte, platelet and bone marrow megakaryocyte number, restored physiological norepinephrine levels and prevented arterial thrombosis in BDNFMet/Met mice. Finally, a norepinephrine reuptake-inhibitor desipramine rescued the prothrombotic phenotype and the behavioural impairments in BDNFMet/Met mice.

Conclusion(s): The α2-ADR pathway might represent a potential pharmacological target to concomitantly treat depression and reduce platelet hyperactivation and thrombosis in the carriers of the BDNFVal66Met polymorphism.