Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse

P. Larsson, I. Alwis, Be'eri Niego, M. Sashindranath, P. Fogelstrand, M. C. L. Wu, L. Glise, M. Magnusson, Maria Daglas, N. Bergh, S. P. Jackson, R. L. Medcalf, S. Jern

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

Essentials * Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. * The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. * Valproic acid increased tissue plasminogen activator expression in vascular endothelium. * Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. Summary Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.
Original languageEnglish
Pages (from-to)2496-2508
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume14
Issue number12
DOIs
Publication statusPublished - 23 Nov 2016

Keywords

  • fibrinolysis
  • HDAC inhibitor
  • thrombosis
  • tissue-type plasminogen activator
  • valproic acid

Cite this

@article{1fff2d58b91949038a3a0b382db9faec,
title = "Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse",
abstract = "Essentials * Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. * The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. * Valproic acid increased tissue plasminogen activator expression in vascular endothelium. * Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. Summary Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.",
keywords = "fibrinolysis, HDAC inhibitor, thrombosis, tissue-type plasminogen activator, valproic acid",
author = "P. Larsson and I. Alwis and Be'eri Niego and M. Sashindranath and P. Fogelstrand and Wu, {M. C. L.} and L. Glise and M. Magnusson and Maria Daglas and N. Bergh and Jackson, {S. P.} and Medcalf, {R. L.} and S. Jern",
year = "2016",
month = "11",
day = "23",
doi = "10.1111/jth.13527",
language = "English",
volume = "14",
pages = "2496--2508",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "12",

}

Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse. / Larsson, P.; Alwis, I.; Niego, Be'eri; Sashindranath, M.; Fogelstrand, P.; Wu, M. C. L.; Glise, L.; Magnusson, M.; Daglas, Maria; Bergh, N.; Jackson, S. P.; Medcalf, R. L.; Jern, S.

In: Journal of Thrombosis and Haemostasis, Vol. 14, No. 12, 23.11.2016, p. 2496-2508.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse

AU - Larsson, P.

AU - Alwis, I.

AU - Niego, Be'eri

AU - Sashindranath, M.

AU - Fogelstrand, P.

AU - Wu, M. C. L.

AU - Glise, L.

AU - Magnusson, M.

AU - Daglas, Maria

AU - Bergh, N.

AU - Jackson, S. P.

AU - Medcalf, R. L.

AU - Jern, S.

PY - 2016/11/23

Y1 - 2016/11/23

N2 - Essentials * Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. * The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. * Valproic acid increased tissue plasminogen activator expression in vascular endothelium. * Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. Summary Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.

AB - Essentials * Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. * The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. * Valproic acid increased tissue plasminogen activator expression in vascular endothelium. * Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. Summary Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.

KW - fibrinolysis

KW - HDAC inhibitor

KW - thrombosis

KW - tissue-type plasminogen activator

KW - valproic acid

UR - http://www.scopus.com/inward/record.url?scp=85005965502&partnerID=8YFLogxK

U2 - 10.1111/jth.13527

DO - 10.1111/jth.13527

M3 - Article

VL - 14

SP - 2496

EP - 2508

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

SN - 1538-7933

IS - 12

ER -