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Eur Heart J. 2017 May 7;38(18):1426-1435. doi: 10.1093/eurheartj/ehv655.

BDNFVal66met polymorphism: a potential bridge between depression and thrombosis.

Author information

1
Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
2
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
3
Department of Cardiac Surgery, Operative Unit of Cardiac Surgery and Translational Research, Policlinico San Donato IRCCS, Milan, Italy.
4
Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY, USA.

Abstract

Aims:

Epidemiological studies strongly suggest a link between stress, depression, and cardiovascular diseases (CVDs); the mechanistic correlation, however, is poorly understood. A single-nucleotide polymorphism in the BDNF gene (BDNFVal66Met), associated with depression and anxiety, has been proposed as a genetic risk factor for CVD. Using a knock-in mouse carrying the BDNFVal66Met human polymorphism, which phenocopies psychiatric-related symptoms found in humans, we investigated the impact of this SNP on thrombosis.

Methods and results:

BDNFMet/Met mice displayed a depressive-like phenotype concomitantly with hypercoagulable state and platelet hyperreactivity. Proteomic analysis of aorta secretome from BDNFMet/Met and wild-type (WT) mice showed differential expression of proteins involved in the coagulation and inflammatory cascades. The BDNF Met allele predisposed to carotid artery thrombosis FeCl3-induced and to death after collagen/epinephrine injection. Interestingly, transfection with BDNFMet construct induced a prothrombotic/proinflammatory phenotype in WT cells. SIRT1 activation, using resveratrol and/or CAY10591, prevented thrombus formation and restored the physiological levels of coagulation and of platelet markers in BDNFMet/Met mice and/or cells transfected with the Met allele. Conversely, inhibition of SIRT1 by sirtinol and/or by specific siRNA induced the prothrombotic/proinflammatory phenotype in WT mice and cells. Finally, we found that BDNF Met homozygosity is associated with increased risk of acute myocardial infarction (AMI) in humans.

Conclusion:

Activation of platelets, alteration in coagulation pathways, and changes in vessel wall protein expression in BDNFMet/Met mice recapitulate well the features occurring in the anxiety/depression condition. Furthermore, our data suggest that the BDNFVal66Met polymorphism contribute to the individual propensity for arterial thrombosis related to AMI.

KEYWORDS:

BDNFVal66Met polymorphism; Depression; Platelet; Thrombosis; Vascular inflammation

PMID:
26705390
PMCID:
PMC6251610
DOI:
10.1093/eurheartj/ehv655
[Indexed for MEDLINE]
Free PMC Article

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