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 inWT 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1426-1435 |
| Number of pages | 10 |
| Journal | European Heart Journal |
| Volume | 38 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - May 1 2017 |
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Keywords
- BDNFVal66Met polymorphism
- Depression
- Platelet
- Thrombosis
- Vascular inflammation
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
BDNFVal66met polymorphism : A potential bridge between depression and thrombosis. / Amadio, Patrizia; Colombo, Gualtiero I.; Tarantino, Eva; Gianellini, Sara; Ieraci, Alessandro; Brioschi, Maura; Banfi, Cristina; Werba, José P.; Parolari, Alessandro; Lee, Francis S.; Tremoli, Elena; Barbieri, Silvia S.
In: European Heart Journal, Vol. 38, No. 18, 01.05.2017, p. 1426-1435.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - BDNFVal66met polymorphism
T2 - A potential bridge between depression and thrombosis
AU - Amadio, Patrizia
AU - Colombo, Gualtiero I.
AU - Tarantino, Eva
AU - Gianellini, Sara
AU - Ieraci, Alessandro
AU - Brioschi, Maura
AU - Banfi, Cristina
AU - Werba, José P.
AU - Parolari, Alessandro
AU - Lee, Francis S.
AU - Tremoli, Elena
AU - Barbieri, Silvia S.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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 inWT 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.
AB - 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 inWT 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.
KW - BDNFVal66Met polymorphism
KW - Depression
KW - Platelet
KW - Thrombosis
KW - Vascular inflammation
UR - http://www.scopus.com/inward/record.url?scp=85019769623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019769623&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehv655
DO - 10.1093/eurheartj/ehv655
M3 - Article
AN - SCOPUS:85019769623
VL - 38
SP - 1426
EP - 1435
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 18
ER -