Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells

Abstract

A reduced capacity for acute tissue-type plasminogen activator (t-PA) release is likely to be associated with an impaired endogenous defense against intravascular thrombosis. Efficient approaches to pharmacologically restore a defective t-PA release have been lacking, but recent observations suggest that histone deacetylase inhibitors (HDACis) enhance t-PA production in vitro. HDACis have diverse chemical structures and different HDAC-enzyme sub-class targeting. We here compared the effects of several clinically used HDACis on t-PA production in endothelial cells. Human umbilical vein endothelial cells were exposed to a panel of 11 different HDACis and t-PA mRNA and protein levels were quantified. All HDACis dose-dependently stimulated t-PA mRNA and protein expression with similar maximal efficacy but with different potencies. Already at low concentrations, the majority of inhibitors caused significant and sustained effects on t-PA production. In addition, selected HDACis were capable of normalizing t-PA production when suppressed by the inflammatory cytokine TNF-α. We conclude that HDACis targeting classical HDAC enzymes are powerful inducers of t-PA expression in cultured endothelial cells and could be promising candidates for pharmacological modulation of endogenous fibrinolysis in man.

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

“…While VPA treatment has been demonstrated to alter t-PA gene expression through increase in gene transcription and synthesis of t-PA, leading to increased constitutive releases of t-PA from cultured human endothelial cells through a HDACi effect [ 15 , 16 ], this is the first report of an effect of HDACi on t-PA release capacity in man with atherosclerotic disease. We have previously shown in an in vivo porcine model, that t-PA release across the coronary vascular bed increased in response to a HDACi treatment.…”

Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man

“…We have previously demonstrated a marked upregulation of the t-PA-gene expression by VPA in vitro mainly through its HDAC inhibitory effect [17] , [18] . The upregulation in cultured human endothelial cells was reflected by both increased mRNA and protein levels.…”

“…Pharmacological tools to directly target the endogenous fibrinolytic system have been lacking. Research by us and others has shown that the t-PA-gene is sensitive to epigenetic control, and several histone deacetylase (HDAC) inhibitors markedly upregulate the t-PA-gene expression in vitro [17] , [18] , [19] . Amongst all the identified and developed HDAC inhibitors, valproic acid (VPA) is already clinically well-established as one of the most commonly used antiepileptic drugs worldwide [20] .…”

Histone Deacetylase Inhibitor Treatment Increases Coronary t-PA Release in a Porcine Ischemia Model

“…Previously in vitro findings have demonstrated that VPA in lower doses can increase t-PA release, and in higher doses cause manifold increase in t-PA release [23], [24]. The mechanism has been confirmed to be VPA's inhibitory effect on the enzyme histone deacetylase, which leads to induction of t-PA transcription in different cell types [23], [28].…”

“…Our group and others have recently demonstrated that the expression of the t-PA gene is dramatically induced by substances affecting histone acetylation, histones that are in complex with DNA in the chromosomes and thus appears to be under epigenetic control [21]–[24]. Increased acetylation of histones occurs through blocking of the enzyme histone deacetylase with histone deacetylase inhibitors (HDACi) [25], [26].…”