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Am J Physiol Heart Circ Physiol 279: H2116-H2123, 2000;
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Vol. 279, Issue 5, H2116-H2123, November 2000

Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts

Jian-Wei Gu1, Bruce R. Ito2, Amanda Sartin1, Nan Frascogna1, Michael Moore1, and Thomas H. Adair1

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% O2) but increased VEGF by an additional 27% during mild hypoxia (10% O2). 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


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