Active and passive mechanical properties of human saphenous and canine femoral and saphenous vein segments were measured in vitro to assess the degree of pressure-dependent venous myogenic tone (% change in diameter, physiological saline solution vs. Ca(2+)-free solution) in these vessels. Stepwise elevation of intraluminal pressure from 2 to 20 mmHg caused an active myogenic response, which was calcium dependent. Side branches of human saphenous veins (OD at 20 mmHg: 1.92 +/- 0.15 mm control; 2.41 +/- 0.18 mm relaxed) displayed a larger degree of myogenic tone (approximately 25%) compared with dog saphenous (OD: 2.84 +/- 0.16 mm control; 2.89 +/- 0.16 mm relaxed) and femoral (OD: 3.56 +/- 0.32 control; 3.66 +/- 0.31 mm relaxed) veins (2-3%). This alteration in myogenic tone results in over 120% change in lumen capacity for the human saphenous vein, whereas for the dog saphenous and femoral veins, the change in lumen capacity is less than 10%. The vessels showed a constriction to norepinephrine as well as a reversible dilation to Ca(2+)-free perfusion. These results support the hypothesis that an active myogenic response may play an important role in the regulation of vascular capacity in the human saphenous vein, which is subject to substantial pressure variations due to changing orthostatic loads.
Objective
The aim of this study was to identify epigenetic factors that are
implicated in the pathogenesis of rheumatoid arthritis (RA) and to explore
the therapeutic potential of the targeted inhibition of these factors.
Methods
PCR arrays were utilized to investigate the expression profile of
genes that encod key epigenetic regulator enzymes. Mononuclear cells from RA
patients and mice were monitored for gene expression changes, in association
with arthritis development in murine models of RA. Selected genes were
further characterized by quantitative real-time PCR, Western blot and flow
cytometry methods. The targeted inhibition of the upregulated enzymes was
studied in arthritic mice.
Results
A set of genes with arthritis-specific expression was identified by
the PCR arrays. Aurora kinase A and B, both of which were highly expressed
in arthritic mice and treatment naïve RA patients, were selected for
detailed analysis. Elevated Aurora kinase expression was accompanied with an
increased phosphorylation of histone H3, which promotes proliferation of T
lymphocytes. Treatment with VX-680, a pan-Aurora kinase inhibitor, promoted
B cell apoptosis, provided significant protection against the onset, and
attenuated the inflammatory reactions in arthritic mice.
Conclusions
Arthritis development is accompanied the changes in the expression of
a number of epigenome-modifying enzymes. Drug-induced downregulation of the
Aurora kinases, among other targets, seems to be sufficient to treat
experimental arthritis. Development of new therapeutics that target the
Aurora kinases can potentially improve RA management.
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