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Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity

Mario Lorenz^*, Bernd Hewing^*, Jingyi Hui, Angela Zepp^*, Gert Baumann^*, Albrecht Bindereif, Verena Stangl^* and Karl Stangl^*,1

^* Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité – Universitätsmedizin Berlin, CCM, Germany; and

Institut für Biochemie, Justus-Liebig-Universität Giessen, Germany

¹Correspondence: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité – Universitätsmedizin Berlin, CCM, Charitéplatz 1, D-10117 Berlin, Germany. E-mail: karl.stangl{at}charite.de

NO, the product of endothelial NOS (eNOS), is a major regulator of vascular homeostasis and a critical factor in preventing cardiovascular diseases. We previously established a positive correlation between the number of variable CA repeats in intron 13 of human eNOS and the risk of coronary artery disease, and demonstrated that these polymorphic CA repeats function as a length-dependent splicing enhancer. By 5'-RACE polymerase chain reaction (PCR), we detected three splice variants containing novel 3' splice sites within intron 13—termed eNOS13A, eNOS13B, and eNOS13C—which share the first 13 exons of human eNOS and the same polyadenylation site at the end of the novel exon. When translated, all these splice variants would result in truncated proteins lacking eNOS activity. Coexpression of full-length eNOS with eNOS13A diminished eNOS enzyme activity in COS-7 cells by formation of heterodimers. The splice variants were expressed in endothelial cells and various human tissues. Finally, we demonstrate, using minigene transfection, that the expression of the eNOS13A splice variant is increased with high CA repeat numbers in intron 13. These data suggest a new mechanism for the regulation of eNOS activity and NO production in the cardiovascular system by truncated, dominant-negative splice variants of human eNOS.—Lorenz M., Hewing B., Hui J., Zepp A., Baumann G., Bindereif A., Stangl V., Stangl K. Alternative splicing in intron 13 of the human eNOS gene: A potential mechanism for regulating eNOS activity

Key Words: NOS • endothelium • NO • CA repeats

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