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- Title
Absence of adenosine-induced relaxation in A2A adenosine receptor-KO mouse aorta: role of CYP 2C9 and CYP 4A.
- Authors
Nayeem, Mohammed A.; Falck, J. R.; Ledent, C.; Ponnoth, D. S.; Ansari, H. R.; Sakhalkar, S. P.; Mustafa, S. J.
- Abstract
Epoxygenation, hydroxylation by CYP 450s and activation of kinases may involve in A2Aadenosine receptor (AR)-mediated response. We hypothesize that CYP 2C9 plays a role in A2A AR endothelium-dependent relaxation (EDR) of mouse aorta. Concentration-response curve (10-11-10-5M) for adenosine (AD) analog, NECA was obtained. A2A AR-WT aorta had a higher relaxation (+74.09 ± 7.22 %, p<0.05) to ACh vs. A2A AR-KO (+50.26 ± 3.93%). E (-) denuded aorta showed a decrease (+2.66±1.58%, p<0.05) in Ach-induced relaxation vs. intact E (+) in WT. NECA caused a relaxation in WT (+34.21 ± 4.36% at 10-7 M, p<0.05) vs. contraction in KO (-17.45 ± 3.39%, at 10-7 M). Differences in NECA responses were noted in E (+) (+34.21 ± 4.36% at l0-7 M, p<0.05) vs. E (-), (-5.64 ± 4.02%, at 10-7 M). 1-ABT (CYP 2C9 inhibitor, 5 µM) changed from a relaxation to contraction to NECA (-25.70 ± 4.75% at 10-6 M, p<0.05) in WT. Similar results were obtained with another CYP2C9 inhibitor, MS-PPOH (10 µM, -22.74 ± 5.11% at 10-6 M, p<0.05) in WT, while no change was observed with NECA in 1-ABT and MS-PPOH in KO (p>0.05). CYP 2C9 was detected in WT (p<0.05) while CYP 4A, PKC-ε and p44/p42 MAPK were detected in KO (p<0.05). Data suggest that CYP 2C9 may play a role in A2A AR mediated-EDR. The data further suggest that the lack of A2A AR leads to less functional endothelium and overexpression of CYP 4A, PKC-ε and p44/p42 MAPK which may lead to contraction. Supported by NIH HL027339 and GM31278
- Subjects
ADENOSINES; HYDROXYLATION; PROTEIN kinases; ENDOTHELIUM; AORTA; LABORATORY mice
- Publication
FASEB Journal, 2007, Vol 21, Issue 6, pA1381
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.6.a1381-a