期刊
BIOLOGICAL CHEMISTRY
卷 389, 期 10, 页码 1333-1338出版社
WALTER DE GRUYTER & CO
DOI: 10.1515/BC.2008.152
关键词
camptothecin; human umbilical vein endothelial cells (HUVECs); inflammation; nitric oxide; TG003
资金
- Deutsche Forschungsgemeinschaft (DFG) [GRK 865, SFB-TR19]
Nitric oxide (NO) is synthesized by endothelial nitric oxide synthase (eNOS) and plays an important role in vascular homeostasis and cardiovascular diseases. It has recently been shown that increased expression of alternatively spliced eNOS isoforms eNOS 13A, B and C and heterodimerization with 'full-length' eNOS is associated with a decreased eNOS activity. The regulatory pathways enabling this phenomenon are completely unknown. This study examined the effect of Cdc2-like kinases and DNA topoisomerase I on eNOS splicing in TNF-alpha-induced human umbilical vein endothelial cells (HUVECs). We found that inhibition of DNA topoisomerase I, but not Cdc2-like kinases, prevents the TNF-alpha-induced increase in eNOS isoform expression and NO reduction in HUVEC. Moreover, we show that the inhibition of DNA topoisomerase I or the Cdc2-like kinases differently modulates the phosphorylation of the serine/arginine-rich proteins SRp75 and SRp55. Our results demonstrate, for the first time, that DNA topoisomerase I but not Cdc2-like kinases serves as an important regulator of the differential eNOS isoform expression in endothelial cells, thereby modulating the TNF-alpha-induced eNOS activity switch.
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