title: BDNFVal66met polymorphism: a potential bridge between depression and thrombosis.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amadio
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Gualtiero I
authors.initials: GI
authors.lastname: Colombo
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Tarantino
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gianellini
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ieraci
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Brioschi
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Banfi
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: José P
authors.initials: JP
authors.lastname: Werba
authors.affiliation: Department of Cardiac Surgery, Operative Unit of Cardiac Surgery and Translational Research, Policlinico San Donato IRCCS, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Parolari
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.|Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: Centro Cardiologico Monzino, IRCCS, Via Parea 4, Milan 20138, Italy.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics; D001011:Aorta / Q000502:physiology; D001777:Blood Coagulation / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002339:Carotid Arteries / Q000502:physiology; D002341:Carotid Artery Thrombosis / Q000235:genetics; D003866:Depressive Disorder / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015539:Platelet Activation / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000494:pharmacology; D013927:Thrombosis / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D010975:Platelet Aggregation Inhibitors; D011956:Receptors, Cell Surface; C426856:SorCS2 protein, mouse; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: BDNFVal66Met polymorphism; Depression; Platelet; Thrombosis; Vascular inflammation