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Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts
Ist Teil von
American journal of physiology. Heart and circulatory physiology, 2000-11, Vol.279 (5), p.H2116-H2123
Ort / Verlag
United States
Erscheinungsjahr
2000
Quelle
MEDLINE
Beschreibungen/Notizen
1 Angiogenesis Research Laboratories, Department of
Physiology and Biophysics, Center for Excellence in
Cardiovascular-Renal Research, University of Mississippi Medical
Center, Jackson, Mississippi 39216; and 2 Metabasis
Therapeutics, Inc., San Diego, California 92121
We tested whether increased
endogenous adenosine produced by the adenosine kinase inhibitor GP-515
(Metabasis Therapeutics) can induce vascular endothelial growth factor
(VEGF) expression in cultured rat myocardial myoblasts (RMMs). RMMs
were cultured for 18 h in the absence (control) and presence of
GP-515, adenosine (Ado), adenosine deaminase (ADA), or GP-515 + ADA. GP-515 (0.2-200 µM) caused a dose-related increase in VEGF
protein expression (1.99-2.84 ng/mg total cell protein); control
VEGF was 1.84 ± 0.05 ng/mg. GP-515 at 2 and 20 µM also
increased VEGF mRNA by 1.67- and 1.82-fold, respectively. ADA (10 U/ml)
decreased baseline VEGF protein levels by 60% and completely blocked
GP-515 induction of VEGF. Ado (20 µM) and GP-515 (20 µM) caused a
59 and 39% increase in VEGF protein expression and a 98 and 33%
increase in human umbilical vein endothelial cell proliferation,
respectively, after 24 h of exposure. GP-515 (20 µM) had no
effect on VEGF protein expression during severe hypoxia (1%
O 2 ) but increased VEGF by an additional 27% during mild
hypoxia (10% O 2 ). These results indicate that raising
endogenous levels of Ado through inhibition of adenosine kinase can
increase the expression of VEGF and stimulate endothelial cell
proliferation during normoxic and hypoxic conditions.
endothelial cells; adenosine deaminase; vascular maintenance
factor; adenosine receptors; growth factors; angiogenesis; GP-515; vascular endothelial growth factor