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J. Biol. Chem., Vol. 282, Issue 21, 15652-15666, May 25, 2007

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Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase^*

Jason E. Fish¹, Charles C. Matouk, Elizabeth Yeboah, Sian C. Bevan, Mukarram Khan^¶, Kedar Patil, Michael Ohh^¶, and Philip A. Marsden, Recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and supported by Heart and Stroke Foundation of Canada Grant MOP T5658^¶2

From the Department of Medical Biophysics, the Renal Division and Department of Medicine, St. Michael's Hospital, and the ^¶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

The destabilization of endothelial nitric-oxide synthase (eNOS) mRNA in hypoxic endothelial cells may be important in the etiology of vascular diseases, such as pulmonary hypertension. Recently, an overlapping antisense transcript to eNOS/NOS3 was implicated in the post-transcriptional regulation of eNOS. We demonstrate here that expression of sONE, also known as eNOS antisense (NOS3AS) or autophagy 9-like 2 (APG9L2), is robustly induced by hypoxia or functional deficiency of von Hippel-Lindau protein. sONE is also up-regulated in the aortas of hypoxic rats. In hypoxic endothelial cells, sONE expression negatively correlates with eNOS expression. Blocking the hypoxic induction of sONE by RNA interference attenuates the fall in both eNOS RNA and protein. We provide evidence that the induction of sONE primarily involves transcript stabilization rather than increased transcriptional activity and is von Hippel-Lindaubut not hypoxia-inducible factor 2-dependent. We also demonstrate that sONE transcripts are enriched in the nucleus of normoxic cells and that hypoxia promotes an increase in the level of cytoplasmic and polyribosome-associated, sONE mRNA. The finding that eNOS expression can be regulated by an overlapping cis-antisense transcript in a stimulus-dependent fashion provides evidence that sense/antisense interactions may play a previously unappreciated role in vascular disease pathogenesis.

Received for publication, August 31, 2006 , and in revised form, March 28, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Recipient of a Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada.

² To whom correspondence should be addressed: University of Toronto, Medical Sciences Bldg., Rm. 7358, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-2441; Fax: 416-978-8765; E-mail: p.marsden{at}utoronto.ca.

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