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PMID:16276418

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Citation

Ward, ME, Toporsian, M, Scott, JA, Teoh, H, Govindaraju, V, Quan, A, Wener, AD, Wang, G, Bevan, SC, Newton, DC and Marsden, PA (2005) Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J. Clin. Invest. 115:3128-39

Abstract

We tested the hypothesis that induction of neuronal NO synthase (nNOS) impairs vascular smooth muscle contractility after hypoxia. nNOS protein was increased in aorta, mesenteric arterioles, pulmonary arteries, brain, and diaphragm from rats exposed to 8% O2 for 48 hours and in human aortic SMCs after hypoxic incubation (1% O2). Ca-dependent NO synthase activity was increased in endothelium-denuded aortic segments from hypoxia-exposed rats. N-nitro-L-arginine methyl ester enhanced the contractile responses of endothelium-denuded aortic rings and mesenteric arterioles from hypoxia-exposed but not normoxic rats (P < 0.05). The hypoxia-inducible mRNA transcript expressed by human cells was found to contain a novel 5'-untranslated region, consistent with activation of transcription in the genomic region contiguous with exon 2. Translational efficiency of this transcript is markedly increased compared with previously described human nNOS mRNAs. Transgenic mice possessing a lacZ reporter construct under control of these genomic sequences demonstrated expression of the construct after exposure to hypoxia (8% O2, 48 hours) in the aorta, mesenteric arterioles, renal papilla, and brain. These results reveal a novel human nNOS promoter that confers the ability to rapidly upregulate nNOS expression in response to hypoxia with a functionally significant effect on vascular smooth muscle contraction.

Links

PubMed PMC1265848 Online version:10.1172/JCI20806

Keywords

Animals; Anoxia/enzymology; Aorta, Thoracic/metabolism; Blotting, Western; Genes, Reporter; Genetic Variation; Humans; Immunohistochemistry; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitric Oxide Synthase Type I/biosynthesis; Nitric Oxide Synthase Type I/genetics; Promoter Regions, Genetic; Protein Biosynthesis/physiology; RNA, Messenger/biosynthesis; Rats; Rats, Sprague-Dawley

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NOS1

involved_in

GO:0001666: response to hypoxia

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:NOS1

involved_in

GO:0001666: response to hypoxia

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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