Borges de Oliveira-Junior Edgar, Thomazzi Sara Maria, Rehder Jussara, Antunes Edson, Condino-Neto Antonio
Department of Pediatrics, Faculty of Medical Sciences, State University of Campinas Medical School, Campinas (SP), Brazil.
Eur J Pharmacol. 2007 Jul 12;567(1-2):43-9. doi: 10.1016/j.ejphar.2007.04.018. Epub 2007 Apr 22.
We investigated the effects of the 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) on the NADPH oxidase activity, gp91(phox) gene expression, cyclic guanosine-3',5'-monophosphate (cGMP) and cyclic adenosine-3',5'-monophosphate (cAMP) levels in the human myelomonocytic THP-1 cell line. THP-1 cells treated with BAY 41-2272 (0.3-10 microM) for 48 h significantly increased the superoxide anion (O(2)(-)) release. This increase was not affected when cells were pre-treated with the specific cGMP-phosphodiesterase inhibitor zaprinast, the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (ODQ), the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl) adenine (SQ 22,536) or the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). In addition, BAY 41-2272 (3 and 10 microM; 48 h) was able to increase gp91(phox) gene expression on THP-1 cells. The pre-treatment with zaprinast, 3-isobutyl-l-methyl-xanthine (IBMX; 0.5 mM), ODQ, SQ 22,536 or l-NAME caused no additional effect on the expression of gp91(phox) evoked by BAY 41-2272. Treatment of THP-1 cells with BAY 41-2272 caused a significant increase in cGMP and cAMP levels. Our findings show that BAY 41-2272 caused a significant increase on the O(2)(-) release and gp91(phox) gene expression by THP-1 cells, and an elevation of intracellular cGMP and cAMP levels. However, we could not detect a clear correlation between both O(2)(*-) release and gp91(phox) gene expression with activation of cGMP and cAMP signaling pathways.
我们研究了5-环丙基-2-[1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-基]-嘧啶-4-胺（BAY 41-2272）对人骨髓单核细胞THP-1细胞系中NADPH氧化酶活性、gp91(phox)基因表达、环鸟苷酸-3',5'-单磷酸（cGMP）和环腺苷酸-3',5'-单磷酸（cAMP）水平的影响。用BAY 41-2272（0.3 - 10 microM）处理THP-1细胞48小时后，超氧阴离子（O(2)(-)）释放显著增加。当细胞用特异性cGMP磷酸二酯酶抑制剂扎普司特、可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-α]喹喔啉-1-酮（ODQ）、腺苷酸环化酶抑制剂9-(四氢-2-呋喃基)腺嘌呤（SQ 22,536）或一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸甲酯（L-NAME）预处理时，这种增加不受影响。此外，BAY 41-2272（3和10 microM；48小时）能够增加THP-1细胞上gp91(phox)基因的表达。用扎普司特、3-异丁基-1-甲基黄嘌呤（IBMX；0.5 mM）、ODQ、SQ 22,536或L-NAME预处理对BAY 41-2272诱导的gp91(phox)表达没有额外影响。用BAY 41-2272处理THP-1细胞导致cGMP和cAMP水平显著升高。我们的研究结果表明，BAY 41-2272导致THP-1细胞的O(2)(-)释放和gp91(phox)基因表达显著增加，以及细胞内cGMP和cAMP水平升高。然而，我们未能检测到O(2)(*-)释放和gp91(phox)基因表达与cGMP和cAMP信号通路激活之间存在明显的相关性。
