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18. Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression

Author

Reitsma, PH, Larsson, P, Ulfhammer, E, Magnusson, M, Bergh, N, Lunke, S, El-Osta, A, Medcalf, RL, Svensson, P-A, Karlsson, L, Jern, S, Reitsma, PH, Larsson, P, Ulfhammer, E, Magnusson, M, Bergh, N, Lunke, S, El-Osta, A, Medcalf, RL, Svensson, P-A, Karlsson, L, and Jern, S

Abstract

AIMS: Stimulated release of tissue-type plasminogen activator (t-PA) is pivotal for an intravascular fibrinolytic response and protects the circulation from occluding thrombosis. Hence, an impaired t-PA production is associated with increased risk for atherothrombotic events. A pharmacological means to stimulate the production of this enzyme may thus be desirable. We investigated if the anti-epileptic drug valproic acid (VPA) is capable of enhancing t-PA expression in vitro in vascular endothelial cells, and further examined if its histone deacetylase (HDAC)-inhibitory activity is of importance for regulating t-PA expression. METHODS AND RESULTS: Human endothelial cells were exposed to valproic acid and t-PA mRNA and protein levels were quantified. Potential changes in histone acetylation status globally and at the t-PA promoter were examined by western blot and chromatin immunoprecipitation. Valproic acid dose-dependently stimulated t-PA mRNA and protein expression in endothelial cells reaching a 2-4-fold increase at clinically relevant concentrations and 10-fold increase at maximal concentrations. Transcription profiling analysis revealed that t-PA is selectively targeted by this agent. Augmented histone acetylation was detected at the t-PA transcription start site, and an attenuated VPA-response was observed with siRNA knock of HDAC3, HDAC5 and HDAC7. CONCLUSIONS: Valproic acid induces t-PA expression in cultured endothelial cells, and this is associated with increased histone acetylation at the t-PA promoter. Given the apparent potency of valproic acid in stimulating t-PA expression in vitro this substance may be a candidate for pharmacological modulation of endogenous fibrinolysis in man.

Published
2012

22. Interrelation of cardiac and vascular structure in young men with borderline hypertension

Author

A. Bergbrant, L. Hansson, and Jern S

Subjects
Adult, Male, medicine.medical_specialty, Cardiac output, Megalencephalic leukoencephalopathy with subcortical cysts, Adolescent, Cardiac Volume, Heart Ventricles, Hemodynamics, Blood Pressure, Left ventricular hypertrophy, Ventricular Function, Left, Internal medicine, medicine, Humans, Body surface area, business.industry, Blood flow, medicine.disease, Blood Pressure Monitors, medicine.anatomical_structure, Endocrinology, Blood pressure, Echocardiography, Hypertension, Vascular resistance, Body Constitution, Hypertrophy, Left Ventricular, Cardiology and Cardiovascular Medicine, business
Abstract

It is not established whether left ventricular hypertrophy and structural vascular changes are primary phenomena or secondary consequences of raised blood pressure. In this study we investigated 54 borderline hypertensive men (BH) (SBP 140-160 mmHg and/or DBP 84-95 mmHg) and 20 normotensive men (NC) (SBP 110-130 mmHg and DBP 60-80 mmHg), recruited from an unbiased population sample (age 20 +/- 2 years). Blood pressure (BP) levels were confirmed by i.a. BP recordings. Left ventricular mass (LVM) was determined with M-mode echocardiography and minimal vascular resistance (Rmin) was calculated from the blood flow in the calf and forearm after maximal ischaemic work. Central haemodynamics were assessed by intra-arterial blood pressure recordings and cardiac output determinations by the dye dilution technique. In the BH group, LVM and Rmin were strongly correlated to body size, especially weight and body surface area. However, LVM and Rmin were only weakly correlated to blood pressure. In the normokinetic BH subgroup (NBH) (n = 38) minimal forearm vascular resistance was significantly higher than in the hyperkinetic BH individuals (HBH) (n = 16), indicating the presence of structural vascular changes in the former. Furthermore, in the NBH group there was a significant correlation between LVM and Rmin both in the calf (r = 0.490 P = 0.002) and in the forearm (r = 0.520 P = 0.001). This association remained after correction for body size. No such correlation was seen in the HBH subgroup or in the NC group. The present study does give long-reaching conclusions as regards the aetiological factors underlying the cardiovascular remodelling. However, our data show that (1) cardiovascular changes appear early in the course of blood pressure elevation, (2) the cardiac and vascular changes develop in parallel, and (3) structural remodelling is not solely explained by the degree of blood pressure elevation since blood pressure was similar in the two BH subgroups. Thus, other factors than blood pressure appear to be important determinants of structural adaptation in mildly hypertensive states.

Published
1993

25. LETTER TO THE EDITOR

Author

Wall U, Ladenvall P, Jern S, and C. Jern

Subjects
Genetics, Text mining, business.industry, Tissue type, Locus (genetics), Single-nucleotide polymorphism, Biology, business, Plasminogen activator, Genetics (clinical)
Published
2001
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