Effects of the Cdc2-like kinase-family and DNA topoisomerase I on the alternative splicing of eNOS in TNF-alpha-stimulated human endothelial cells

Biological Chemistry
Andreas EisenreichU Rauch

Abstract

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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Citations

Aug 9, 2011·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Wan-Jung LuJoen-Rong Sheu
Mar 11, 2011·Circulation Journal : Official Journal of the Japanese Circulation Society·Andreas EisenreichUrsula Rauch
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Aug 5, 2020·Life Sciences·Andreas EisenreichReinhold Kreutz
May 22, 2020·Redox Biology·Benjamin N GantnerMarcelo G Bonini
Feb 1, 2011·Chemistry & Biology·Oleg FedorovStefan Knapp

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