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Pulmonary and Critical Care Medicine Section, Providence Veterans Affairs Medical Center, Brown University School of Medicine, Providence, Rhode Island 02908
Endothelial cell (EC)
apoptosis is important in vascular injury, repair, and angiogenesis.
Homocysteine and/or adenosine exposure of ECs causes apoptosis.
Elevated homocysteine or adenosine occurs in disease states such as
homocysteinuria and tissue necrosis, respectively. We examined the
intracellular signaling mechanisms involved in this pathway of EC
apoptosis. Inhibition of protein tyrosine phosphatase (PTPase)
attenuated homocysteine- and/or adenosine-induced apoptosis and
completely blocked apoptosis induced by the inhibition of
S-adenosylhomocysteine hydrolase with MDL-28842. Consistent with this finding, the tyrosine kinase inhibitor genistein enhanced apoptosis in adenosine-treated ECs. Adenosine significantly elevated the PTPase activity in the ECs. Mitogen-activated protein kinase activities were examined to identify possible downstream targets
for the upregulated PTPase(s). Extracellular signal-regulated kinase
(ERK) 1 activity was slightly elevated in adenosine-treated ECs,
whereas ERK2, c-Jun NH2-terminal kinase-1, or p38
activities differed little. The mitogen-activated protein kinase-1
inhibitor PD-98059 enhanced DNA fragmentation, suggesting that
increased ERK1 activity is a result but not a cause of apoptosis in
adenosine-treated ECs. Adenosine-treated ECs had diminished p38
activity compared with control cells; this effect was blunted on PTPase
inhibition. These results indicate that PTPase(s) plays an integral
role in the induction of EC apoptosis upon exposure to homocysteine
and/or adenosine, possibly by the attenuation of p38 activity.
vascular endothelium; signal transduction; nucleotides; homocysteine
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