Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript

Robb, G. Brett; Carson, Andrew R.; Tai, Sharon C.; Fish, Jason E.; Singh, Sundeep; Yamada, Takahiro; Scherer, Stephen W.; Nakabayashi, Kazuhiko; Marsden, Philip A.

doi:10.1074/jbc.m400271200

Cited by 133 publications

(138 citation statements)

References 67 publications

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“…In addition, eNOS mRNA is known to be stable and have a long half-life at 16-48 hr [40,47]. Since newly transcribed eNOS mRNA is subject to posttranscriptional regulation at multiple levels, its transcription kinetics and stability change before it becomes translated into protein [13,34,39]. Translation of eNOS mRNA to eNOS protein in olfactory cells may be repressed or promoted at different sites, which may enable eNOS protein to be expressed in the olfactory cells with particular olfactory receptors as mentioned above.…”

Section: Discussionmentioning

confidence: 99%

Localization of eNOS in the Olfactory Epithelium of the Rat

Endo

Yamamoto

Yamaguchi-Yamada

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. Nitric oxide (NO) is a free radical and produced from L-arginine by nitric oxide synthase (NOS). Since NO is recently suggested to be involved in olfactory perception, the expression of eNOS, an isoform of NOS, was examined in the rat olfactory epithelium. The activity of NADPH-diaphorase was also examined as a marker of NOS. In the dorsomedial region of the nasal cavity, intensely positive reactions for NADPH-diaphorase were observed in the entire cytoplasm of sensory cells (olfactory cells). By immunohistochemistry, intensely positive reactions for eNOS were also found in the dorsomedial region of the nasal cavity. These reactions were observed on the free border of the olfactory epithelium. By immunoelectron microscopy, positive reactions for eNOS were found in the cilia of olfactory cells. In addition, in situ hybridization analysis of the olfactory epithelium revealed the expression of eNOS mRNA in the olfactory cells. These results indicate the presence of eNOS in the olfactory cells of the rat, and differential expression of eNOS in the olfactory epithelium depending on the regions of the nasal cavity. In addition, NO produced by eNOS may be involved in olfactory perception in the cilia of olfactory cells.KEY WORDS: eNOS, NADPH-diaphorase, nitric oxide, olfactory epithelium, rat.J. Vet. Med. Sci. 73(4): 423-430, 2011 Nitric oxide (NO) is a free radical with many functions in the cardiovascular, nervous, and immune systems [2]. Biologically, NO is produced from L-arginine by nitric oxide synthase (NOS). NOS is divided into 3 types of major isoforms, i.e., neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). The nNOS and eNOS are constitutive forms of NOS and mainly expressed in the neuronal and endothelial cells, respectively. The iNOS is an inducible form of NOS and mainly expressed in macrophages [15].Primary function of NO is the activation of soluble guanylyl cyclase (sGC) to increase cGMP levels [1]. In the cilia of the rat sensory cells (olfactory cells), it is reported that odorant-stimulus induces the increase of cGMP levels and that specific NOS inhibitor L-N G -nitro arginine or NO scavenger hemoglobin inhibits this increase [4]. These findings indicate that odorant-stimulus induces NO production in the rat olfactory cells. Schmachtenberg et al. (2000Schmachtenberg et al. ( , 2003 reported that NO-stimulus induces outward potassium currents in 30 out of 72 olfactory cells and inward potassium currents in 3 out of 54 cells by physiological study [36,37]. In the cilia of rat olfactory cells, moreover, NO-stimulus is reported to activate or inhibit olfactory cyclic nucleotidegated (CNG) channels [5,6,28,36,37]. These reports suggest that NO is produced by the olfactory cells in response to odorant-stimulus, and has inhibitory and/or weakly excitatory effects to the olfactory cells by gating of CNG channel. However, it is still unclear which type of NOS isoforms generates NO in the olfactory cells of the rat. Because it has been reported that iNOS and eNOS are expressed...

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Section: Discussionmentioning

confidence: 99%

Localization of eNOS in the Olfactory Epithelium of the Rat

Endo

Yamamoto

Yamaguchi-Yamada

et al. 2011

The Journal of Veterinary Medical Science

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“…Overexpression of sONE in endothelial cells, which normally express high levels of eNOS but not sONE, resulted in reduced expression of eNOS protein, suggesting that sONE can negatively regulate the expression of eNOS. In contrast, RNA interference-mediated knockdown of sONE in vascular smooth muscle cells resulted in increased expression of eNOS RNA (8).…”

mentioning

confidence: 94%

“…Since two distinct sONE transcripts exist, each originating from a unique transcriptional start site (8), real time RT-PCR was used to quantify the basal and hypoxia-inducible copy number of each transcript in HUVEC. Primers for the long transcript were located in AS exon 4 (5Ј-CCT TCG ATG CGT GGA TTA CAA TG-3Ј and 5Ј-GCA CAC TGG GCT GAG GGT AGG A-3Ј), whereas the exon 7/8 primer set (Table 1) detected total sONE transcripts (i.e.…”

Section: Methodsmentioning

confidence: 99%

“…sONE and eNOS mRNA were reciprocally expressed in cultured cells. Relative to endothelial cells, levels of sONE RNA were found to be elevated in nonendothelial cell types, such as vascular smooth muscle cells (VSMCs), which express very low basal levels of eNOS RNA (8). Overexpression of sONE in endothelial cells, which normally express high levels of eNOS but not sONE, resulted in reduced expression of eNOS protein, suggesting that sONE can negatively regulate the expression of eNOS.…”

mentioning

confidence: 99%

“…We recently identified a natural cis-antisense transcriptional unit to eNOS/NOS3 (8). sONE, also known as NOS3AS/ APG9L2, is oriented tail-to-tail to NOS3, and sONE mRNA is complementary to the eNOS mRNA for 662 nucleotides.…”

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confidence: 99%

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

Fish

Matouk

Yeboah

et al. 2007

Journal of Biological Chemistry

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132

120

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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-Lindau-but 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.

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Genomic landscape of developing male germ cells

Lee

Pang

Rennert

et al. 2009

Birth Defects Research Pt C

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Spermatogenesis is a highly orchestrated developmental process by which spermatogonia develop into mature spermatozoa. This process involves many testis-or male germ cell-specific gene products whose expressions are strictly regulated. In the past decade the advent of high-throughput gene expression analytical techniques has made functional genomic studies of this process, particularly in model animals such as mice and rats, feasible and practical. These studies have just begun to reveal the complexity of the genomic landscape of the developing male germ cells. Over 50% of the mouse and rat genome are expressed during testicular development. Among transcripts present in germ cells, 40% -60% are uncharacterized. A number of genes, and consequently their associated biological pathways, are differentially expressed at different stages of spermatogenesis. Developing male germ cells present a rich repertoire of genetic processes. Tissue-specific as well as spermatogenesis stagespecific alternative splicing of genes exemplifies the complexity of genome expression. In addition to this layer of control, discoveries of abundant presence of antisense transcripts, expressed psuedogenes, non-coding RNAs (ncRNA) including long ncRNAs, microRNAs (miRNAs) and Piwiinteracting RNAs (piRNAs), and retrogenes all point to the presence of multiple layers of expression and functional regulation in male germ cells. It is anticipated that application of systems biology approaches will further our understanding of the regulatory mechanism of spermatogenesis. †

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Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript

Cited by 133 publications

References 67 publications

Localization of eNOS in the Olfactory Epithelium of the Rat

Localization of eNOS in the Olfactory Epithelium of the Rat

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

Genomic landscape of developing male germ cells

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