Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RhoA is an important modulator of endothelial monolayer permeability. Posttranslational carboxyl methylation of small GTPases, such as RhoA and Ras, regulates subcellular localization and GTPase activity, resulting in altered cellular function. In this study, we investigated the role of RhoA carboxyl methylation in modulating endothelial monolayer permeability. We found that inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT) with adenosine plus homocysteine (Ado/HC) or N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) decreased RhoA carboxyl methylation and activation, which correlated with decreased monolayer permeability of bovine pulmonary artery endothelial cells (BPAEC). Conversely, BPAEC stably overexpressing ICMT had enhanced endothelial monolayer permeability, associated with elevated RhoA carboxyl methylation and activation. These results suggest that ICMT modulates endothelial monolayer permeability by altering RhoA carboxyl methylation and activation. In addition, we demonstrated that adenosine deaminase inhibitor not only attenuated, but also rescued, lung edema induced by a non-inflammatory edemagenic agent. Our data suggest that increasing intracellular adenosine is a useful therapeutic strategy against diseases characterized by increased vascular permeability.
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PMID:Pulmonary endothelial cell signaling and function. 1859 49

We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A(1) or A(3) antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A(2A) and A(2B), respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A(2A) and A(2B) receptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A(2A)/A(2B) receptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A(2A) and A(2B) agonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A(2A) and A(2B) receptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by alpha-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.
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PMID:Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement. 2022 81