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(The FASEB Journal. 1998;12:773-790.)
© 1998 FASEB

REVIEW

Expressional control of the `constitutive' isoforms of nitric oxide synthase (NOS I and NOS III)

Ulrich Förstermanna,1, Jean-paul Boissela, and Hartmut Kleinerta

a Department of Pharmacology, Johannes Gutenberg University, D-55101 Mainz, Germany


   ABSTRACT
TOP
 ABSTRACT
`CONSTITUTIVE' AND INDUCIBLE...
 NOS I
 NOS III
 CONCLUSION
 REFERENCES
 
Nitric oxide synthase (NOS) exists in three established isoforms. NOS I (NOS1, ncNOS) was originally discovered in neurons. This enzyme and splice variants thereof have since been found in many other cells and tissues. NOS II (NOS2, iNOS) was first identified in murine macrophages, but can also be induced in many other cell types. NOS III (NOS3, ecNOS) is expressed mainly in endothelial cells. Whereas NOS II is a transcriptionally regulated enzyme, NOS I and NOS III are considered constitutively expressed proteins. However, evidence generated in recent years indicates that these two isoforms are also subject to expressional regulation. In view of the important biological functions of these isoforms, changes in their expression may have physiological and pathophysiological consequences. This review recapitulates compounds and conditions that modulate the expression of NOS I and NOS III, summarizes transcriptional and posttranscriptional effects that underlie these changes, and—where known—describes the molecular mechanisms leading to changes in transcription, RNA stability, or translation of these enzymes.—Förstermann, U., Boissel, J.-P., Kleinert, H. Expressional control of the `constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J. 12, 773–790 (1998)


Key Words: cellular expression • gene structure • transcription factors • transcriptional regulation • RNA stability • protein stability


   `CONSTITUTIVE' AND INDUCIBLE ISOFORMS OF NITRIC OXIDE SYNTHASE
TOP
 ABSTRACT
 `CONSTITUTIVE' AND INDUCIBLE...
NOS I
 NOS III
 CONCLUSION
 REFERENCES
 
IN MAMMALS, THREE ISOFORMS of nitric oxide synthase (NOS)2 have been identified. NOS I (NOS1, ncNOS) is a low-output NOS that is constitutively expressed and whose activity is regulated by Ca2+ and calmodulin. The prototypical enzyme is present in neurons. NOS II (NOS2, iNOS) is a high-output NOS whose expression is induced by cytokines (and other agents) and whose activity is largely or completely Ca2+ independent. The prototypical enzyme is expressed by activated murine macrophages. NOS III (NOS3, ecNOS) is also a low-output NOS that is constitutively expressed and whose activity is regulated by Ca2+ and calmodulin. The prototypical enzyme is being found in endothelial cells. Whereas transcriptional regulation of NOS II has been established for about 10 years, no expressional regulation was originally known for the other two isoforms. More recent evidence suggests, however, that the expression of NOS I and NOS III can also be regulated under various conditions.


   NOS I
TOP
 ABSTRACT
 `CONSTITUTIVE' AND INDUCIBLE...
 NOS I
NOS III
 CONCLUSION
 REFERENCES
 
Cellular expression of NOS I
NOS I was first characterized in, and purified from, rat and porcine cerebellum (1–3). Since then, NOS I was found to have a widespread distribution in specific neurons of the central and peripheral nervous systems. The list of NOS I-containing neurons continues to expand, and to date it is difficult to find an organ that is not innervated by neurons `saying NO' (4). NOS I is likely to play an important role not only in physiologic neuronal functions such as neurotransmitter release, neural development, regeneration, synaptic plasticity, and regulation of gene expression, but also in a variety of neurological disorders in which excessive production of NO leads to neural injury (5). However, NOS I expression is not confined to neuronal cells. In various species, NOS I mRNA transcripts and/or protein have been detected in nonneuronal cell types. Table 1 gives an overview of the neuronal and nonneuronal expression of NOS I.


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  		Table 1. NOS I expression in various tissues and cell types

The subcellular localization of NOS I protein varies greatly among the cell types studied. In neurons, both soluble and particulate protein is found. Depending on the individual study, the particulate enzyme represents between 30 and 60% of the total neuronal NOS I protein (36–38). Differences reported may be explained by shifts of the protein from one fraction to the other during development (as demonstrated in rat brain; see ref 39), by species differences, and by the different assay methods used. In electron microscopy studies of kidney macula densa cells, the neuronal isoform has been seen associated mainly with small vesicles (28). In skeletal muscle, NOS I protein is mostly particulate (23, 40). The particulate localization of part of the NOS I protein is probably due to the PDZ/GLGF motif found in the NH2-terminal sequence of the NOS I protein. This motif participates in protein–protein interactions with several other membrane-associated proteins (41, 42). In neurons, synaptic association of NOS I is mediated by the binding of the PDZ/GLGF motif to the postsynaptic density protein PSD-95 (43) and/or to the related PSD-93 protein (44). N-methyl-D-aspartate (NMDA) receptors are also known to be associated with PSD-95 (45). Colocalization of neuronal NOS and the huntingtin-associated protein (HAP1) has also been reported (46). In fast-twitch skeletal muscle fibers, the muscle-specific isoform (µNOS I) is attached to the sarcolemma–dystrophin complex via the PDZ/GLGF motif and interacts mainly with {alpha}1-synthrophin (47). Recent studies demonstrated a selective loss of sarcolemmal NOS I in mdx mice lacking the endogenous dystrophin. A similar loss of membrane-associated NOS I was seen in Duchenne muscular dystrophy and Becker muscular dystrophy, diseases in which the dystrophin gene is mutated (47–49).

Expressional regulation of NOS I
Increasing evidence indicates that NOS I expression can be dynamically regulated by various physiological or pathological conditions. NOS I mRNA up-regulation seems to represent a general response of neuronal cells to stress induced by a large array of physical, chemical, and biological agents such as heat (50), electrical stimulation (51), light exposure (52, 53), colchicine (54), formalin (55), phenobarbital (56), and allergic substances (57). A similar response is observed in the rat paraventricilar nucleus and adrenal cortex during immobilization stress (58, 59) and after mechanical or pathological lesions, including spinal cord, axonal, or nerve injuries (60–62), hypophysectomy (63), or arterial occlusion leading to local ischemia (64, 65). Cellular stress is known to trigger the expression of a number of genes resulting in cellular damage and apoptosis. The observed NOS I up-regulation may, in most cases, represent only one component of the normal cellular stress response. Enhanced NOS I expression is often associated with coinduction of transcription factors such as c-jun (60, 66) and c-fos (67, 68).

A down-regulation of NOS I expression has been documented in guinea pig skeletal muscle and rat brain after in vivo treatment with bacterial lipopolysaccharide (LPS) (25, 69). Treatment of rats with LPS or interferon-{gamma} (IFN-{gamma}) also decreased the expression of NOS I in the brain, stomach, rectum, and spleen (70). However, one conflicting report suggested a transient increase of NOS I mRNA level in the paraventricular nucleus of LPS-treated rats (71).

Physical stimuli regulating NOS I expression
Several in vivo studies in rat suggested a time-dependent increase in NOS I mRNA after hypoxia(72–74). This up-regulation may be due to two distinct mechanisms: a general cellular stress response or a direct activation of the NOS I gene transcription through binding of hypoxia-induced factors to specific cis-acting elements, as seen in erythropoietin and several other hypoxia-induced genes (75). Putative `BACGTSSK' binding sites for the hypoxia-inducible factor-1 (HIF-1) can be detected along the NOS I genomic sequence, but the functionality of these motifs has not yet been determined.

In neurons that constitute the osmoresponsive circuit of the rat hypothalamo-hypophysal system, expression of the NOS I gene was up-regulated by changes in plasma osmolarity occurring, for instance, during chronic salt loading (76) or water deprivation (77). In contrast, a low-salt diet resulted in an increase in NOS I mRNA in the rat kidney, with a coordinate up-regulation of renal expression of renin and angiotensinogen (78, 79). In addition, angiotensinogen gene knockout mice displayed high levels of NOS I in the macula densa of the kidney (80).

Regulation of NOS I expression by neurotransmitters and hormones
NOS I expression also appears to be regulated by changes in neuronal activity (81). In cerebellar granule cells, inhibition of the glutamatergic transmission drastically increased NOS I expression (82). In neurons of the central nervous system (CNS), NOS I is often colocalized with NMDA receptors (83, 84), which are known to effectively mediate Ca2+ influx.

NOS I expression can also be triggered by sex hormones. It has been demonstrated that estradiol and pregnancy could induce NOS I expression in several tissues in the rat (85–87). However, increase in NOS I mRNA was not apparent in the lamina terminalis and the hypothalamo-neurohypophysial system of the rat during pregnancy (88). In male rats, testosterone treatment has been described to stimulate expression of the neuronal isoform in the penis (89).

Corticosterone treatment results in up-regulation of heme oxygenase-2 and a concomitant decrease of NOS I transcription in rat brain (90). Lithium and tacrine, a cholinesterase inhibitor used to treat symptoms of Alzheimer's disease, increase the expression of NOS I synergistically in the hippocampus of the rat. This effect could be inhibited by corticosterone (91).

Developmental regulation of NOS I expression
Spatial and temporal NOS I expression patterns occurred during development of the nervous system (92–94) and the lung (26, 95). These changes seem to correlate with differential susceptibility of the cells, at particular developmental stages, toward specific inductors such as nerve growth factor (96), estrogens (97), neurotransmitters, and neurotrophins (98). Ogura et al. (99) showed that the NOS I mRNA level was increased in a human neuroblastoma cell line after trans-retinoic acid-induced neuronal differentiation. In skeletal muscle, a developmental switch from NOS I to the alternative transcript µNOS I (see below) has been reported concomitant with myotube fusion (24). Moreover, an enhanced expression of NOS I is generally observed with postnatal development and aging (100, 101).

Chromosomal localization, genomic structure, and cDNA of NOS I
Kishimoto et al. (102) mapped the human NOS I gene to the q14-qter position of chromosome 12 using human–rodent hybrid cells and a human NOS I cDNA fragment in Southern blots. Fluorescence in situ hybridization studies allowed investigators to further define the precise location of the gene to 12q24.2 (103) and to 12q24.2–24.3 (104). Homologous genes of mouse and rat have been assigned to chromosome 5 (105) and chromosome 12 (106), respectively.

The genomic structure of NOS I is well documented for the enzyme from human brain (9, 107). Several mouse genomic clones have also been obtained for the targeted disruption of the neuronal NOS, but no sequence data have been divulged (108). Sequence data of mouse first exons are also available (109). A yeast artificial chromosome clone containing part of the rat neuronal NOS I transcriptional cluster has recently been published (110). Brain-type NOS I cDNAs have been isolated from rat (111) and mouse (112). Recently, the rabbit NOS I cDNA sequence has been deposited in Genbank (accession number: U91584). For the coding sequence, the three mammalian sequences show 86 to 88% of identity with the human NOS I at the nucleotide level.

The human NOS I gene is present as a single copy in the haploid human genome and reveals a highly complex structural organization ( Fig. 1). The locus is scattered over a region greater than 200 kb. The nucleotide sequence corresponding to the major neuronal mRNA transcript is encoded by 29 exons. The full-length open reading frame codes for a protein of 1434 amino acids with a predicted molecular mass of 160.8 kDa, in good agreement with results obtained by protein purification (1–3). Comparison of the NOS I locus with the genomic organization of the two other NOS isoforms, NOS II (113) and NOS III (103, 114), demonstrates a striking similarity in the size of the exons and the location of the intronic splice junctions, suggesting that the three isoforms derive from duplications of a common ancestor.



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  		Figure 1. Genomic organization of the human neuronal nitric oxide synthase (NOS I) (adapted from refs 9, 10, 30). Exons are numbered and illustrated by black boxes. The nucleotide sequence corresponding to the major neuronal mRNA transcript is encoded by 29 exons. Many exons are of relatively small size, ranging from 59 to 266 bp. However, two large exons are present, exon 2 (1145 bp) and exon 29 (2150 bp), that include the translation initiation and termination sites, respectively. Two described transcriptional clusters (neuronal and testis specific) are schematized above and below the genomic map. Due to the presence of multiple promoters and transcription start sites, different first exons (5'-exons) can be used. All first exons of the neuronal cluster seem to splice to the common exon 2; therefore, one unique translation product corresponding to the full-length NOS I protein is likely to be assembled. Transcription from the testis-specific cluster, located between exon 3 and exon 4, gives rise to mRNA transcripts encoding for NH2-truncated enzymes. Possible cassette exon deletions of exon 10, or exons 9 and 10, are circled. Reported cassette exon insertions in the full-length NOS I are boxed: Tex 2 from the testis transcriptional cluster, and the µNOS I insert located between exons 16 and 17 of the human NOS I. Locations for repetitive elements are indicated; the human gene contains three sets of dinucleotide CA repeats and one (CG)n island. Members of the Alu repetitive sequences, indicated by triangles, are also found scattered at several locations along the human NOS I gene.

Genotypic analyses of normal individuals demonstrated the existence of multiple alleles that vary in size (9, 10, 115). In particular, alleles of NOS I that differ in the number of CA/TG dinucleotide repeats in the 5'-flanking region may show differences in basal promoter activity. CA repeats are known to favor formation of left-hand Z-DNA. Z-DNA sequences are often present in DNA regions critical for the regulation of transcription and replication (116).

Diversity of NOS I transcripts
Cloning and/or characterization of NOS I cDNAs from different human and rodent tissues have revealed structural and allelic mRNA diversity. Multiple broadly distributed, tissue-specific, or developmentally regulated mRNA transcripts have been reported. The different transcripts arise from three different mechanisms: 1) the initiation by different transcriptional units containing alternative promoters, 2) cassette exon deletions or insertions, and 3) the use of alternate polyadenylation signals. Combinations of two or three of these mechanisms account for the variety of NOS I transcripts described.

Transcriptional units and alternative promoters
The usage of various alternative promoters seems to be one of the main characteristic of the NOS I gene ( Fig. 2). To date, two major transcriptional clusters (neuronal and testis-specific) have been distinguished for the human gene. The neuronal cluster is located upstream from exon 2. At least eight different first exons and the corresponding 5'-flanking promoter sequences have been detected. They are distributed over a large region (>= 200 kb) of genomic DNA. Major transcription sites were found located >= 25 kb upstream from exon 2 (9, 10, 22, 117, 118). The different first exons appear to splice to the common exon 2 that contains the initiator ATG codon. Therefore, the protein encoded by the different mRNA species is the same and corresponds to the full-length, wild-type NOS I protein. Nevertheless, the use of alternative promoters is a versatile mechanism that can influence gene expression by various means (119). The level of transcriptional initiation can be different: the processing, localization, translation efficiency, and half-life of the mRNAs with various leader exons may differ. Alternative promoters could have distinct tissue specificities or developmental regulation and could respond differently to stimuli. Indeed, in situ hybridization with antisense cRNAs localized the different exon 1 variants to distinct cell populations, indicating that cell type-specific transcription/splicing factors may control NOS I expression (10).



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  		Figure 2. Model of alternative promoter usage. Initiation of transcription from different first exons (E1a to E1c) driven by distinct promoters, associated with alternatively spliced exons, results in various mRNA transcripts with divergent 5'-UTRs. In the case of the neuronal NOS I transcriptional cluster, all the alternative exons (E1) appear to be finally spliced to the same exon 2 (E2) that contains the initiator codon. Therefore, only one protein is translated.

Multiple first exons have also been reported for the mouse NOS I gene, and cDNA sequencing revealed at least five distinct mRNA transcripts (109). Some transcripts are expressed in a tissue- or developmentally specific manner. A recent report demonstrated the existence of at least three transcripts of the rat NOS I gene that also arise from alternative splicing (110). A high degree of tissue and developmental specificity in expression is observed. One of these alternative transcripts is specifically induced during neuronal differentiation of the rat PC12 cell line.

Two closely linked human promoters and the corresponding first exons (named 5'1 and 5'2 by the authors) have been particularly well studied (117, 118). Each has a distinct promoter activity and can independently drive the expression of a reporter gene in transfection studies. Exon 5'1 is embedded within a (CG)n island and its associated promoter lacks an identifiable TATA box, resulting in the initiation of transcription at multiple sites within the exon. On the other hand, an initiator element located upstream from exon 5'2 leads to a limited number of transcription starts. Reverse transcription/polymerase chain reaction demonstrated high levels of transcriptional expression for both exon 5'1 and exon 5'2 in the cerebellum and low expression in skeletal muscle. Yet a high expression level of a 5'1+5'2 promoter complex–luciferase fusion plasmid was obtained in transfected HeLa cells, suggesting that this region lacks the critical cis-acting element (or elements) responsible for CNS-restricted expression. The levels of NOS I mRNA and protein are greatly decreased in neuronal cell lines with reduced Oct-2 expression, a transcription factor member of the POU family. Cotransfection experiments with Oct-2 expression vectors and NOS I promoter-reporter gene constructs resulted in specific activation of the 5'1 promoter (120). However, no canonical ATGCAAAT Oct-2 binding site can be detected in the sequence of the NOS I promoter used in that study (120).

In normal human testis, transcription can initiate from a genomic region located within intron 3 (30) (see Fig. 1). A novel NOS I mRNA transcript, with a 5' terminus encoded for by two new exons (named Tex 1 and Tex 2) spliced to exon 4 (of the full-length NOS I), appears to be expressed in the testis at a level comparable to that of the full-length neuronal enzyme. A minor transcript containing a unique 95 bp exon Tex 1b 5' of exon Tex 2 was also detected. Analysis of the two mRNAs predicted the translation to occur at an ATG within exon 5, giving rise to a protein (TnNOS) of 1098 amino acids, with a calculated molecular mass of 125 kDa. Functional studies of the TnNOS stably transfected in CHO-K1 cells indicate that this protein is calcium dependent and exhibits a catalytic activity comparable to that of full-length NOS I. TnNOS lacks the NH2-terminal extension of the full-length NOS I, which contains the PDZ/GLGF protein–protein interaction motif. In stably transfected CHO-K1 cells, the TnNOS and full-length NOS I were distributed identically among cytosolic and particulate fractions. This suggests that either the PDZ/GLGF motif is not the only structure conveying membrane association of NOS I, or CHO-K1 cells lack the expression of some important partner proteins.

The mouse neuronal NOS-{gamma} (nNOS-{gamma}) is an analog of the human TnNOS. Nevertheless, the molecular mechanism involved in its synthesis is not the same. In nNOS {Delta}/{Delta} mice with a targeted deletion of exon 2 (108), two alternative transcripts (ß and {gamma}) are produced at very low levels. These use different first exons (1a and 1b, respectively) spliced to a common exon 3 (43). Translation of nNOS-{gamma} is initiated at the same ATG codon within exon 5 as the human TnNOS, giving rise to a similar 125 kDa protein. Translation of nNOS-ß is initiated at a CTG initiation codon within exon 1a, generating a 136 kDa NOS protein with six new NH2-terminal amino acids. A noticeable expression of nNOS-ß transcript occurs in the striatum and cortex of nNOS {Delta}/{Delta} mice. The nNOS-ß transcript has also been detected in many areas of the brain of wild-type mice (particularly in the ventral cochlear nuclei), where it produces a catalytically active protein (121). This protein, which lacks the PDZ/GLGF domain, has been found mainly in the cytosolic fraction (109). Recently, several human brain tumors were shown to express an alternatively spliced form of NOS I that comigrates with nNOS-ß and also lacks exon 2 (109).

Cassette exon deletions
Cassette deletions of exon 10 and exons 9/10 were detected in human neuronal NO synthase mRNA transcripts (9, 10). The deletion of exon 10 introduces a stop codon 16 bp downstream of the splice junction, leading potentially to a novel truncated 560 amino acid protein. Excision of exons 9 and 10 results in a 315 bp in frame deletion, possibly leading to a protein lacking 105 amino acids. Low expression of this mRNA transcript was observed in various human and mouse brain tissues and in neuroblastoma cell lines (112, 122). It remains to be determined whether these cassette deletions are translated in vivo. Olgivie et al. (123) identified a subshortened inactive NOS I variant (termed NOS I144) that is expressed during synaptogenesis. However, even though the molecular weight was in agreement with an excision of exons 9 and 10, the structure of this deletion mutant has not been demonstrated at the nucleotide level. Using antisense probes targeting specifically the full-length NOS I transcript or the truncated form lacking exons 9 and 10, Kolesnikov et al. (124) investigated the role of these two splice variants in morphine tolerance. Whereas antisense probes to the full-length NOS I prevented development of morphine tolerance, antisense probes targeting the truncated form blocked morphine analgesia and shifted the morphine dose-response curve by more than twofold to the right (124). The NOS I-related dNOS cloned recently from Drosophila exhibits the same 315 bp deletion and is fully active (125).

A small mRNA of 2.5 kb has also been detected in mouse adult testis (109). This transcript is thought to translate into a protein encoding only the reductase domain of NOS I. No further characterization of this protein has been reported.

Cassette exon insertions
A 102 bp insertion between exons 16 and 17 has been reported for the rat neuronal NOS gene, resulting in the translation of a fully active µNOS I (`muscle NOS I') protein that contains a 34 amino acid addition (24, 31) (see Fig. 1). µNOS I is expressed in the rat skeletal muscle, heart, penis, urethra, and prostate (31). It coexists with the `classical' NOS I in rat pelvic plexus and bladder, and is detectable at low levels in the cerebellum. In culture, its expression coincides with myotube fusion. Most of the µNOS I in muscle is found complexed with dystrophin at the sarcolemma of intrafusal fibers in muscle spindles (126). The 102 bp insert was also found in human penile RNA and its transcription from intron 16 was established (31).

A cassette insertion of exon Tex 2 between exons 3 and 4 of the full-length NOS I was isolated when screening a human testis cDNA library and was subsequently found in a variety of other human tissues (30) (see Fig. 1). The insertion of the corresponding 56 bp leads to a frameshift and introduces a stop codon 371 bp downstream of the splice junction within exon 6. In vivo translation of the resulting COOH-truncated, 407 amino acid protein has not yet been demonstrated.

Alternate polyadenylation signals
The human NOS I exon 29 contains three potential polyadenylation signals. The site for cleavage and poly (A) addition fluctuates over a 200 bp region, with a predominant site located 6449 bp downstream of the initiator methionine (9). Exon 29 also contains a (CA)n repeat sequence. Genotypic analysis of normal individuals demonstrated the existence of multiple alleles of various sizes, depending on the number of (CA)n repeats. The effect of these 3'-end variations on mRNA transcription, processing, stability, or subcellular targeting is currently unknown.

Characterization of the 5'-flanking sequences of NOS I
A 1634 nucleotide sequence from the human neuronal transcriptional cluster has been obtained (9). In its 3' part, this DNA fragment encompasses potential first exons. This region contains a TATA box and two inverted CAAT boxes. Potential binding sites for transcription factors are found such as AP-2, transcriptional enhancer factor-1/M-CAT binding factor, CREB (cAMP-responsive element binding protein)/ ATF (activating transcription factor)/cFOS, Ets, NF-1 (nuclear factor 1), and nuclear factor {kappa}B (NF-{kappa}B) -like sequences. In the human testis transcriptional cluster, analyses 1800 bp upstream of the Tex 1 exon and 1705 bp upstream of the Tex 1b exon indicate that the two genomic regions lack a typical TATA box (30). A CAAT box is located 330 bp upstream from exon Tex 1b. Numerous potential cis-acting DNA elements have been detected: Sp-1, ATF/CRE-like sequences, NF-{kappa}B, activator protein 1 (AP-1), and AP-2. In addition, a variety of cis-regulatory elements implicated in testis-specific transcription are evident including transcription factor GATA and GATA-like sites, p53 half-element, an Ets binding site, Pu box, polyomavirus enhancer activator 3 (PEA3) sequences, myocyte-specific enhancer factor 2 motif, and an insulin response element site. However, no functional characterization of the neuronal or testis NOS I transcriptional regulatory regions has yet been published.


   NOS III
TOP
 ABSTRACT
 `CONSTITUTIVE' AND INDUCIBLE...
 NOS I
 NOS III
CONCLUSION
 REFERENCES
 
Cellular expression of NOS III
NOS III was first identified in endothelial cells (127, 128). Using a specific antibody to NOS III, immunohistochemical studies located the enzyme to various types of arterial and venous endothelial cells in many tissues, including human tissues (129). NOS III expression has also been demonstrated in several nonendothelial cell types, including neurons of the rat hippocampus and other rat brain regions, and in human motor neurons (130, 131) ( Table 2).


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  		Table 2. NOS III expression in various cell types

NOS III has been shown to be targeted to Golgi membranes and plasmalemmal caveolae, a complex process probably dependent on myristylation, palmitoylation, and tyrosine phosporylation of the enzyme as well as protein–protein interactions with caveolins (151, 152). Experiments with NOS III green fluorescent protein (GFP) chimeras revealed that the first 35 amino acids (and fatty acylation sites) of NOS III are sufficient to target GFP into the Golgi region of NIH 3T3 cells (153). NOS III has also been shown to interact with caveolins, a family of transmembrane proteins that form a key structural component of the caveolae (151, 152, 154). This interaction seems to negatively regulate NOS III activity (154). Mislocalization of NOS III caused by mutation of the N-myristoylation or cysteine palmitoylation sites reduces intracellular enzyme activity, suggesting that intracellular targeting of the NOS III is critical for endothelial NO production (155).

Endothelium-derived NO is a physiologically significant vasodilator and an inhibitor of platelet aggregation and adhesion. In addition, vascular NO can prevent leukocyte adhesion to the endothelium by down-regulating the leukocyte adhesion glycoprotein complex CD11/CD18. Finally, NO has also been shown to inhibit the proliferation of vascular smooth muscle cells (for a review, see refs 156, 157). Therefore, endothelial NO is likely to represent a protective anti-atherogenic principle, and up- or down-regulation of endothelial NOS could have important consequences for vascular homeostasis. Several compounds and conditions implicated in vascular physiology and/or pathophysiology can modify the expression of NOS III. These compounds and conditions are discussed below.

Expressional regulation of NOS III
Shear stress
Exercise training and shear stress produced by the flowing blood up-regulate NOS III expression (158–160) ( Table 3). The enhancement of NOS III mRNA expression in bovine aortic endothelial cells (BAEC) by shear stress was not inhibited by dexamethasone, inhibitors of protein tyrosine kinases, or inhibition of G-protein signaling. In contrast, chelation of intracellular calcium in BAEC reduced shear stress induction of NOS III mRNA by almost 70% (160). A putative shear stress-responsive element (6 bp core sequence 5'-GAGACC-3') has been described in the promoter sequence of the human and bovine NOS III gene (see below) (103, 161). However, the functionality of this element has not been proven.


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  		Table 3. Conditions or compounds that modify NOS III expression

Oxygen tension and hypoxia
For pulmonary endothelial cells, there seems to be consensus that hypoxia down-regulates NOS III expression. In human primary pulmonary artery endothelial cells (162), cultured porcine pulmonary artery endothelial cells (163), and bovine pulmonary artery endothelial cells (164), hypoxia reduced NOS III mRNA and/or protein. At least in the bovine species, this was attributed to both a decreased rate of transcription and a destabilization of the NOS III mRNA (164). The down-regulation of NOS III may be implicated in pulmonary ventilation-perfusion coupling (with poorly ventilated areas of the lung being poorly perfused).

In nonpulmonary endothelial cells, the findings are more controversial. In BAEC, Arnet et al. (165) saw an up-regulation of NOS III mRNA and protein expression in cells incubated at low oxygen tension (1%). In this study, hypoxia did not change the stability of NOS III mRNA. On the other hand, the promoter activity of a 1.6 kb DNA fragment of the 5'-flanking sequence of the human NOS III gene was enhanced by hypoxia (165). Therefore, enhanced NOS III expression in response to hypoxia is likely to result from enhanced promoter activity (165). However, the human NOS III promoter contains no homology to the published binding sequence of the hypoxia induced transcription factor HIF-1. Also, Zhang et al. (166) reported up-regulation of endothelial NOS III immunoreactivity in cerebral blood vessels during cerebral ischemia. Other reports, however, demonstrated reductions of NOS III expression in human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells exposed to low oxygen tension (167, 168) ( Table 3). This reduction in NOS III expression was reported to result from decreased stability of NOS III mRNA and reduced NOS III promoter activity (167).

Proliferation and growth status
It has been shown that NOS III mRNA and protein is increased in growing vs. resting BAEC (169) ( Table 3). This enhanced NOS III expression was found to be the result of a greater stability of the NOS III mRNA in proliferating compared with confluent BAEC (169). Growth-arrested BAEC showed enhanced expression of a protein that interacts with the 3'-UTR of the bovine NOS III mRNA and destabilized the mRNA (170). In contrast to these results, Flowers et al. (171) reported a reduction of NOS III mRNA and protein in asynchronously proliferating cultures and wounded endothelial cell monolayers compared with quiescent nonproliferating cells ( Table 3). Because run-on experiments showed no changes in transcription rates, the reduction of NOS III mRNA in proliferating cells was attributed to NOS III mRNA destabilization (171). The reason for these discrepant findings between the two groups is not clear at this time.

Cytokines and bacterial LPS
In BAEC and HUVEC, tumor necrosis factor-{alpha} (TNF-{alpha}) down-regulates NOS mRNA, protein, and activity (158, 172). The down-regulation of NOS III mRNA expression by TNF-{alpha} in HUVEC has been ascribed to a destabilization of NOS III mRNA with no effect on transcription (173). In bovine endothelial cells, this destabilization seems to result from the specific interaction of a TNF-{alpha}-induced protein with the 3'-UTR (untranslated retion) sequence of the NOS III mRNA (174). In contrast, in resident astrocytes of the CNS, Barna et al. (148) described an enhancement of NOS III immunoreactivity when mice were treated intraperitoneally with IL-12, a potent activator of IFN-{gamma} and TNF-{alpha} production. These authors also found a cytokine-mediated activation of NOS III expression after exposure of C6 glioma cells to IL-12, IFN-{gamma}, and TNF-{alpha} (148). C6 glioma cells express NOS III constitutively (cf Table 2).

Kaku et al. (175) described an up-regulation of NOS III mRNA expression and NOS III promoter activity from treatment of BAEC with INF-{alpha}/ß and LPS. Similarly, Bucher et al. (176) found an up-regulation of NOS III mRNA expression in the liver of LPS- or lipoteichoic acid (LTA)-treated rats. They concluded that NOS III may be an even more important source of NO than NOS II in the liver after stimulation with LPS or LTA (176). In contrast, LPS injection into rats has been shown to reduce NOS III mRNA expression (along with NOS I mRNA expression) in aorta, heart, and lung (69). Another study demonstrated a down-regulation of NOS III in gastrointestinal mucosa after LPS treatment of rats (144). Therefore, cytokines and LPS seem to regulate NOS III expression in different ways depending on the cytokine combination, species, and cell type analyzed.

Estrogens and other sex steroids
There are several reports that estrogens can up-regulate the expression of NOS III mRNA and protein. In guinea pigs, near-term pregnancy and treatment with estradiol (but not progesterone) increased calcium-dependent NOS activity in various tissues. Both pregnancy and estradiol enhanced NOS III mRNA (along with NOS I mRNA) in guinea pig skeletal muscle (177). An increase in NOS III mRNA has also been seen in the aortas of pregnant or estrogen-treated, but not progesterone- or testosterone-treated, rats (178). Kidneys from female rats contain more NOS III protein than those of male or oophorectomized female rats (179). Estrogen replacement therapy increased medullary NOS III levels in oophorectomized animals (179). On the other hand, in in vitro studies with ovine fetal pulmonary artery endothelial cells, estrogens enhanced NOS III activity, but no change in NOS III mRNA expression was detected (180). A study of bovine endothelial cells claimed that 17{alpha}-ethinyl estradiol did not enhance the expression of NOS III, but increased the release of bioactive NO by inhibiting superoxide anion production (181). Studies performed in our own laboratory (182) demonstrated that estrogens did enhance NOS III mRNA and protein expression in permanent human endothelial EA.hy 926 cells. The increased NOS III expression resulted from increased NOS III promoter activity with unchanged mRNA stability. In the absence of a bona fide estrogen-responsive element in the human NOS III promoter (see below), increased NOS III promoter activity may result from an enhanced binding activity of transcription factor SV40 virus promoter specific transcription protein 1 (Sp1, which is essential for the human NOS III promoter; see below) (182).

Growth factors
Recent evidence indicates that an incubation of endothelial cells with certain growth factors may up-regulate NOS III expression. Incubation or BAEC with transforming growth factor-ß1 (TGF-ß1) produced a modest up-regulation of NOS III mRNA and protein (183). This up-regulation of NOS III expression was reported to result from enhanced promoter activity (see below). Deletion of a putative NF-1 binding site in the bovine NOS III promoter abolished TGF-ß1-enhanced promoter activity (183). Similarly, incubation of BAEC with basic fibroblast growth factor enhanced NOS III mRNA, protein, and activity (184).

Oxidized low density lipoproteins and lysophosphatidylcholine
The effects of oxidized low density lipoprotein (oxLDL) on NOS III expression are complex. In human saphenous vein endothelial cells, oxLDL (50 µg/ml) has been reported to reduce NOS III mRNA levels by decreasing the half-life of mRNA (185). The effect of oxLDL (50 µg/ml) on NOS III promoter activity was biphasic as measured in nuclear run-on experiments. Treatment with oxLDL decreased NOS III promoter activity by about 25% in the first 6 h, followed by a 1.8- and 2.2-fold increase at 12 and 24 h, respectively (185) ( Table 3). Hirata et al. (186) found an up-regulation of NOS III mRNA in BAEC incubated with low concentrations of oxLDL (10 µg/ml), whereas high concentrations (100 µg/ml) reduced mRNA levels after 24 h. Similar responses were seen with lysophosphatidylcholine, another component of atherogenic lipoproteins (186) ( Table 3). In HUVEC, lysophosphatidylcholine up-regulated NOS III expression (187) ( Table 3). Using nuclear run-on assays and reporter gene analyses, this enhanced NOS III expression was shown to result from lysophosphatidylcholine-stimulated NOS III promoter activity (188).

Modulation of protein kinase C activity
Incubation of BAEC (189) or human EA.hy 926 endothelial cells (190) with phorbol esters enhanced NOS III expression. Ohara et al. (189) concluded from their results that down-regulation of PKC by long-term incubation with phorbol esters (or PKC inhibition with staurosporine) enhances NOS III expression. In contrast to these results, in our own experiments with human EA.hy 926 endothelial cells, the time course of phorbol ester-induced enhancement of NOS III expression paralleled PKC activation (190) ( Table 3). Also, specific PKC inhibitors such as bisindolylmaleimide I, Gö 6976, Ro-31–8220, and chelerythrine prevented the phorbol ester-induced enhancement of NOS III expression. Based on transfection experiments with a 3.5 kb human NOS III promoter fragment, the phorbol ester-stimulated enhancement of NOS III expression seems to be a transcriptional event (190).

Additional conditions and compounds that have been described to up- or down-regulate NOS III expression are summarized in Table 3.

Chromosomal localization, genomic structure, and cDNA of NOS III
The human NOS III mRNA is encoded by 26 exons spanning 21–22 kb of genomic DNA (103, 200). The gene is present as a single copy in the haploid human genome. The human NOS III gene has been assigned to the 7q35–7q36 region of chromosome 7 (103). The bovine NOS III gene spans approximately 20 kb of DNA and also contains 26 exons. Two transcription start sites have been determined that are located 170 and 240 base pairs upstream of the methionine translation initiation codon (161).

Full-length NOS III cDNAs have been isolated from human (201, 202), murine (203), bovine (158, 172, 204), and porcine (205) endothelial cells. The deduced amino acid sequences predict proteins of 133 kDa for all species, which is in good agreement with the molecular mass determined by protein purification (128). The homology between the human coding cDNA sequence and those of the other species is around 90%; the identity of the deduced amino acid sequences is about 94%.

Polymorphisms of the NOS III gene and cardiovascular disease
Minisatellite sequences, tandem repeats, and dinucleotide (CA)n repeats have been identified in introns of the human NOS III gene (103, 114, 200). Some studies have attempted to link polymorphisms of these sequences with cardiovascular disease. Bonnardeaux et al. (206) reported that the highly polymorphic (CA)n repeats in intron 13 and two biallelic markers in intron 18 are not associated with essential hypertension. Another study explored the distribution of a 27 bp repeat in intron 4 of the human NOS III gene (207). They found a more common larger allele (with five repeats) and a rarer smaller allele (with four repeats). The study demonstrated a significant association between this polymorphism and coronary artery disease. Patients homozygous for the rare four-repeat allele were more likely to have one or more significantly diseased vessels. The increased risk could be demonstrated only in current and former cigarette smokers; heterozygous individuals (smokers or nonsmokers) had no increased risk of coronary artery disease (207).

Characterization of the 5'-flanking sequences of NOS III
Characterization of the 5'-flanking genomic region of human NOS III indicates that the endothelial NO synthase promoter is `TATA-less' and exhibits proximal promoter elements consistent with a constitutively expressed gene in endothelial cells such as Sp1 and GATA motifs (208). Furthermore, the human NOS III promoter contains consensus sequences for the binding of transcription factors AP-1, AP-2, NF-1, nuclear factor IL6, NF-{kappa}B, and PEA3, as well as CACCC-, CCAAT-, heavy metal-, acute-phase response-, shear stress-, cAMP-response-, retinoblastoma control-, INF-{gamma}-response-, and sterol-regulatory cis elements ( Fig. 3). The promoter sequence also contains several half-sites of the estrogen-responsive element (ERE), but no bona fide EREs are found ( Fig. 3). A functional relevance has been demonstrated for only a few of these potential binding sites. Deletion and mutation analyses revealed an essential role of the Sp1 binding site at position -103 (208). Stimulation of the human NOS III promoter by estrogens in human EA.hy 926 endothelial cells (182) and by lysophosphatidylcholine in HUVEC (188) may result from an enhanced binding activity of transcription factor Sp1. Mutation of the consensus GATA site at position -230 reduced human NOS III promoter activity by about 30% (208). Mutation of the PEA3 binding site at position -26 reduced promoter activity by about 50% (188). Arnet et al. (165) demonstrated an enhanced activity of the human NOS III promoter in transfected bovine endothelial cells exposed to hypoxia. However, the human NOS III promoter contains no homology to an HIF-1 consensus sequence. None of the other consensus sequences described above are known to mediate induction of promoter activity by hypoxia. Phorbol ester incubation of human endothelial cells transfected with a human NOS III promoter-luciferase construct produced an enhancement of promoter activity (190). However, the transcription factors involved are not yet known.



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  		Figure 3. Comparison of the transcription factor binding sites in the bovine and human NOS III promoter (adapted from refs 200, 208). Putative binding sites for transcription factors AP-1 (1), GATA (g or G), NF-1 (n or N), NF-{kappa}B ({kappa}), PEA3 (p or P), and Sp1 (s or S), and of shear stress-induced transcription factors (blood flow, f) are shown. The location of half-sites for the estrogen receptor binding element (e) are also shown. Capital letters indicate binding sites whose function has been demonstrated in transfection (deletion or mutation) or gelshift experiments. 5'-UTR, 5'-untranslated region of the mRNA; cds, protein coding sequence of the mRNA.

Similar to the 5'-flanking sequence of the the human NOS III gene, the known 2.9 kb 5'-flanking sequence of the bovine gene lacks a typical TATA box and contains numerous putative transcription factor binding sites ( Fig. 3). Comparison of the first 1.6 kb 5'-flanking sequence showed 75% nucleotide identity with the corresponding human sequence (161). In reporter gene assays, a bovine promoter fragment (positions -1548 to +240) showed significant basal activity in transfected BAEC. A deletion fragment (positions -1548 to + 192) lacking two putative Sp1 binding sites in the 5'-UTR of the NOS III cDNA lost almost all of its promoter activity, suggesting that transcription factor Sp1 is important for NOS III gene transcription in the bovine species as well. The modest up-regulation of NOS III mRNA by TGF-ß1 in BAEC is likely to be the result of enhanced activity of the bovine NOS III promoter based on increased binding of transcription factor NF-1 to its respective response element (183).


   CONCLUSION
TOP
 ABSTRACT
 `CONSTITUTIVE' AND INDUCIBLE...
 NOS I
 NOS III
 CONCLUSION
REFERENCES
 
Having realized that a pluripotent molecule such as NO is produced by many different cells and probably acts on an equally large number of target cells, it comes as little surprise to learn that nature has also invented a large array of regulatory mechanisms for NO production. The original paradigm that NO is either synthesized by constitutive NO synthases (NOS I and NOS III) or by the inducible NOS II is being challenged by an increasing number of reports that demonstrate expressional regulation for the constitutive enzymes (and constitutive expression of NOS II). Thus, not only the high-output NOS II is turned on transcriptionally to produce NO as a nonspecific weapon of antimicrobial defense, but expressional levels of the servoregulatory, low-output enzymes NOS I and NOS III can also be adjusted to meet local demand. Toward this goal, cells can modify the rate of transcription of these genes, the stability of the transcripts, and probably also their translation. In addition, at least NOS I is subject to cell-specific assembly of alternative exons and expressional control by different promoters. This can lead to NOS Iproteins with different cellular localizations, different catalytic activities, and perhaps different functions. Many of the regulations discussed above make physiological sense: some are still controversial; the molecular mechanism of most is still poorly understood. Together they add to the puzzling diversity of mechanisms controlling NO production.


   ACKNOWLEDGMENTS
 
Research in the authors' laboratory pertaining to this topic was supported by Grant Fo 144/3–2 and SFB 553, Project A1 (to U.F.) from the DeutscheForschungsgemeinschaft.


   FOOTNOTES
 
1 Correspondence: Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55101 Mainz, Germany. E-mail ulrich.forstermann{at}uni-mainz.de

2 Abbreviations: AP-1, activator protein 1; ATF, activating transcription factor; BAEC, bovine aortic endothelial cells; cFOS, mammalian homologue to the FBJ murine osteosarcoma virus oncogene; CNS, central nervous system; CRE, cAMP-responsive element; ERE, estrogen-responsive element; ETS, human analogs to avian acute leukemia virus E26 oncogene; GATA, transcription factor GATA; GFP, green fluorescent protein; GLGF motif, gly-leu-gly-phe motif found in diverse membrane-associated proteins; HIF-1, hypoxia-inducible factor-1; HUVEC, human umbilical vein endothelial cells; IFN-{gamma}, interferon-{gamma}; IL-1, interleukin-1; LPS, lipopolysaccharide; LTA, lipoteichoic acid; NF-1, nuclear factor 1; NF-{kappa}B, nuclear factor {kappa}B; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NOS, nitric oxide synthase; µNOS, muscle-specific isoform; Oct-2, octamer binding factor 2; PEA3, polyomavirus enhancer activator 3; PDZ domain, same as the gly-leu-gly-phe (GLGF) motif; POU, transcription factors containing protein sequences homologous to the mammalian Pit-1, Oct-1, Oct-2, and Caenorhabditis elegans Unc-86 gene products; oxLDL, oxidized low density lipoprotein; Pu box, enhancer DNA sequence of the lymphotropic papovavirus; Sp1, SV40 virus promoter specific transcription protein 1; TGF-ß, transforming growth factor ß; TNF-{alpha}, tumor necrosis factor {alpha}; UTR, untranslated region.


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