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A more recent version of this article appeared on March 1, 2003
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Submitted on July 9, 2002
Revised on October 28, 2002
Accepted on November 18, 2002
1 Pulmonary Vascular Biology Laboratory, Providence Veterans Affairs Medical Center, Brown Medical School, Providence, Rhode Island
* Corresponding author. E-mail address: Sharon_Rounds{at}brown.edu.
Extracellular ATP, adenosine (Ado), and adenosine plus homocysteine (Ado/HC) cause apoptosis of cultured pulmonary artery endothelial cells through the enhanced formation of intracellular S-adenosylhomocysteine and disruption of focal adhesion complexes. Since increased intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine favors inhibition of methylation, we hypothesized that Ado/HC might act by inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT). We found that N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) and N-acetyl-S-farnesyl-L-cysteine (AFC), which inhibit ICMT by competing with endogenous substrates for methylation, caused apoptosis. Transient overexpression of ICMT inhibited apoptosis caused by Ado/HC, UV light exposure, or TNF
. Because the small GTPase, Ras, is a substrate for ICMT and may modulate apoptosis, we also hypothesized that inhibition of ICMT with Ado/HC or AGGC might cause endothelial apoptosis by altering Ras activation. We found that ICMT inhibition decreased Ras methylation and activity and the activation of downstream signaling molecules, Akt, ERK-1, and ERK-2. Furthermore, overexpression of wild type or dominant active H-Ras blocked Ado/HC induced apoptosis. These findings suggest that inhibition of ICMT causes endothelial cell apoptosis by attenuation of Ras GTPase methylation, activation, and its downstream anti-apoptotic signaling pathway.
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