Published online before print September 29, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114207
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(Hypertension. 2008;52:903.)
© 2008 American Heart Association, Inc.
Original Articles |
Nitric Oxide Upregulates Dimethylarginine Dimethylaminohydrolase-2 via Cyclic GMP Induction in Endothelial Cells
From the Department of Clinical and Molecular Endocrinology (M. Saurada, M. Shichiri, Y.H.) and Department of Biosystem Regulation, Institute of Biomaterials and Bioengineering (M.I., H.A.), Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Correspondence to Masayoshi Shichiri, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail mshichiri.cme{at}tmd.ac.jp
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Abstract |
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Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that metabolizes asymmetrical NG,NG-dimethyl-L-arginine (ADMA) and NG-monomethyl-L-arginine (MMA), which are competitive endogenous inhibitors of NO synthase. However, it remains unknown whether NO itself influences DDAH activity and/or ADMA/MMA contents to regulate NO generation via a biofeedback mechanism. The present study was designed to examine the effects of NO on intracellular ADMA and MMA contents and DDAH gene expression levels and enzymatic activities in cultured rat aortic endothelial cells. The NO donors SNAP and NOR3 did not influence DDAH-1 expression but increased DDAH-2 mRNA and protein levels in concentration-dependent manners. SNAP upregulated DDAH enzymatic activity and reduced the MMA and ADMA contents but did not affect the symmetrical NG,N’G-dimethyl-L-arginine and L-arginine levels, thereby negating a mediatory role for system y+ in ADMA/MMA downregulation. The cGMP agonists 8-bromo-cGMP and C-type natriuretic peptide also stimulated DDAH-2 gene and protein expression levels and DDAH activity and increased the amount of nitrite/nitrate released into the culture supernatants. SNAP-induced DDAH-2 gene expression and DDAH activity were significantly inhibited by a protein kinase G inhibitor, KT5823, and a soluble guanylate cyclase inhibitor, ODQ, suggesting a mediatory role for cGMP in NO-induced DDAH-2 expression. Suppression of DDAH-2 mRNA using small interfering RNA technology abrogated NO-induced DDAH-2 expression. These data demonstrate that NO acts on endothelial cells to induce DDAH-2 expression via a cGMP-mediated process to reduce ADMA/MMA. Thus, the DDAH-2-ADMA/MMA-endothelial NO synthase regulatory pathway and NO-induced cGMP constitute a positive feedback loop that ultimately serves to maintain NO levels in the endothelial environment.
Key Words: DDAH-2 • NO • ADMA • MMA • cGMP
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Introduction |
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Endothelium-derived NO generated from L-arginine by endothelial NO synthase (eNOS)1 is well known as a potent vasodilator that plays critical roles in regulating vascular resistance and flow.2 NO inhibits key processes in atherogenesis, such as monocyte adhesion, platelet aggregation, and vascular smooth muscle proliferation.3 Although endothelial vasodilator dysfunctions are likely to be multifactorial, one contributory abnormality appears to be increasing levels of endogenously produced NO synthase (NOS) inhibitors, namely, asymmetrical NG,NG-dimethyl-L-arginine (ADMA) and NG-monomethyl-L-arginine (MMA). These methylarginines compete with L-arginine for NOS to decrease NO production,4 and their accumulation has been implicated in human and experimental cardiovascular diseases. Plasma ADMA concentrations are elevated in patients with hypercholesterolemia,5 hypertension,6 hyperglycemia,7–9 and cigarette smoke exposure.10 Although ADMA levels have been shown to predict the risk of acute coronary events,11 it remains undetermined whether ADMA has a causative role. Although the involvement of MMA has been less well documented, our previous studies suggested its importance as an endogenous NOS inhibitor.12–14 Thus, both ADMA and MMA could serve as endogenous regulators of NO synthesis that may be dysregulated in disease states.
ADMA and MMA are either excreted in the urine or metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH).15 Therefore, ADMA accumulation could be caused by impaired DDAH activity.5 DDAH is an enzyme that metabolizes ADMA and MMA to L-citrulline and dimethylamine or monomethylamine and is composed of 2 isoforms, DDAH-1 and DDAH-2. These isoforms have distinct tissue distributions but similar enzymatic activities.14,16 DDAH-1 is typically found in tissues expressing neuronal NOS, whereas DDAH-2 predominates in tissues containing eNOS.16 Thus, DDAH may play important roles in the regulation of cellular ADMA and MMA levels and subsequent control of NO production. The ADMA and MMA contents under regulation by DDAH have been considered to control eNOS function to determine local NO concentrations, thereby protecting endothelial function in endothelial cells.
The enzymatic activity of purified DDAH protein is known to be reversibly reduced after direct exposure to high concentrations of the NO donor DEANONOate in vitro.17 However, the regulation of DDAH expression by lower concentrations of NO acting on intact cells has not yet been investigated. Therefore, we examined the effects and regulatory mechanisms of NO on the expression and activity of DDAH and the endothelial elaboration of ADMA and MMA.
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Methods |
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For a detailed account of the methods please see the data supplement (available online at http://hyper.ahajournals.org).
Cell Culture
Rat aortic endothelial cells (RAECs) prepared from the thoracic aorta of 6-week-old male Sprague-Dawley rats as described18 were starved with medium containing 0.5% calf serum for 24 hours and used for subsequent experiments unless otherwise stated.
Quantification of mRNA
The rat DDAH-1 and -2 mRNA levels were quantified by TaqMan fluorescence methods. Total RNA was extracted, first-strand cDNA synthesized, and the amplification reaction performed using a LightCycler (Roche Molecular Biochemicals). PCR primers were designed using a Universal probe library (Roche Molecular Biochemicals).
Immunofluorescence Staining
RAECs were fixed, stained with antihuman DDAH-1 antibody (1:1000, Orbigen) or antihuman DDAH-2 antibody (1:1000, Abcam), and visualized with an Alexa Fluor 488-conjugated secondary antibody (1:2000; Molecular Probes). Laser scanning confocal microscopy was performed using an LSM 510 system (Carl Zeiss Microscopy).
Western Blot Analysis
Western blot was performed essentially as described.13 Primary antibodies used recognize DDAH-1 (1:1000, Orbigen), DDAH-2 (1:500, Abcam), and GAPDH (1:3000, Sigma Chemical Co). The data were expressed as the mean ratio of the DDAH-1 or DDAH-2 protein density to the GAPDH density.
Measurement of DDAH Activity
DDAH activity was measured by monitoring the formation of L-[3H]-citrulline from [3H]-MMA (NG-monomethyl-L-arginine[2,3,4-3H]) essentially as described previously.13
Measurement of L-Arginine and Methylarginine Contents
The MMA, ADMA, symmetrical NG,N’G-dimethyl-L-arginine (SDMA), and L-arginine contents in RAECs were determined by high-performance liquid chromatography, as described previously.19
Determination of Nitrite/Nitrate Concentrations
Confluent cultures of RAECs in 10-cm collagen-coated plates were incubated in the presence or absence of the indicated NO donors or cGMP agonists for 48 hours. The levels of nitrite/nitrate (NOx) in the conditioned media were determined using a Total Nitrite/Nitrate Assay kit (Dojindo).
RNA Interference for DDAH-2
A predesigned small interfering RNA for rat DDAH-2 targeting exon 6 of XM579741 was transfected into exponentially growing RAECs, incubated for a further 24 hours, and then starved in medium containing 0.5% calf serum for subsequent experiments.
Statistical Analysis
Data were expressed as means±SEMs. Differences between groups were examined for statistical significance using an unpaired t test or ANOVA with Dunn’s posthoc test, when appropriate. Values of P<0.05 were considered statistically significant.
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Results |
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Induction of DDAH-2 Gene by NO
First, we tested whether the expression levels of the DDAH-1 and DDAH-2 genes were affected by serum and growth factors. We also tested the effect of ionomycin, a Ca2+ ionophore, to determine whether increased intracellular Ca2+ alone would affect gene expression. The steady-state expression level of DDAH-1 mRNA in cultured RAECs was unaffected by 10% serum, ionomycin, or endothelial growth-promoting factors (please see the data supplement). In contrast, the DDAH-2 mRNA level was significantly lower in RAECs cultured under 10% serum than in RAECs starved in 0.5% serum (45.5±8.5% of the level in RAECs growing under 10% serum; P<0.05). The addition of ionomycin or endothelial growth factors also led to decreased DDAH-2 mRNA levels (please see the data supplement).
Next, we examined whether NO donors directly affected the expression levels of the DDAH genes in cultured RAECs. The NO donor SNAP (10–5 mol/L) did not induce any significant change in the DDAH-1 mRNA level (Figure 1A) but markedly increased the DDAH-2 mRNA level in RAECs cultured under 0.5% serum for 24 hours (please see the data supplement). NAP, the inactive precursor of SNAP, had no effect at an equivalent concentration (please see the data supplement). The effects of SNAP on DDAH-2 mRNA upregulation were time (8 to 16 hours) and concentration (10–6 to 10–5 mol/L) dependent in RAECs cultured under 0.5% serum for 24 hours (Figure 1B and 1C) and in 10% serum (data not shown). Another NO donor, NOR3, also concentration dependently (5.0x10–6 to 2.5x10–5 mol/L) increased the DDAH-2 mRNA levels in RAECs cultured under reduced serum conditions (Figure 1D) and in 10% serum (data not shown). SNAP induced DDAH-2 mRNA expression in human umbilical vein endothelial cells and in human retinal endothelial cells cultured under 0.5% serum condition in a concentration-dependent manner (10–6 to 10–5 mol/L) but had no effect on DDAH-1 expression (please see the data supplement). Therefore, subsequent experiments were performed using RAECs cultured under 0.5% serum for 24 hours.
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Mediation of cGMP in NO-Induced DDAH-2 Gene Expression
Because NO increases intracellular cGMP concentrations, we tested whether other cGMP agonists stimulate DDAH-2 gene expression. 8-Bromo-cGMP (10–5 to 10–4 mol/L) and CNP (10–10 to 10–9 mol/L) concentration dependently increased the DDAH-2 mRNA levels in RAECs (please see the data supplement). The magnitude of the maximal DDAH-2 mRNA induction by 8-bromo-cGMP was always lower than that induced by SNAP. To determine whether SNAP-induced DDAH-2 gene expression was mediated via a cGMP pathway, the effects of cGMP blockers were examined. Pretreatment of RAECs with a protein kinase G inhibitor, KT5823 (10–6 mol/L), significantly inhibited SNAP (10–5 mol/L)-induced DDAH-2 gene expression (please see the data supplement). The SNAP- and CNP-induced increases in the DDAH-2 mRNA levels were also suppressed by a soluble guanylate cyclase inhibitor, ODQ (5x10–6 mol/L; please see the data supplement). Therefore, SNAP-induced DDAH-2 gene expression in RAECs is mediated, at least in part, via induction of cGMP.
DDAH-2 Protein Expression
Immunofluorescence analysis did not reveal any appreciable induction of DDAH-1 protein expression after stimulation with SNAP (please see the data supplement). In contrast, SNAP (10–6 to 10–5 mol/L) treatment markedly upregulated DDAH-2 protein levels in RAECs after 24 hours (please see the data supplement). The magnitude of the DDAH-2 signals appeared to become stronger as the SNAP concentration increased. DDAH-2 protein expression was most remarkably induced by SNAP at 24 hours and returned to the baseline level by 48 hours. In addition to the NO donor, the cGMP-elevating reagents 8-bromo-cGMP (10–4 mol/L) and CNP (10–9 mol/L) also induced DDAH-2 protein expression (please see the data supplement). Neutralization experiments using an excess of the peptide antigen corresponding with the epitope of the anti–DDAH-2 antibody resulted in complete disappearance of the intracellular immunofluorescent signals in both untreated RAECs (please see the data supplement) and RAECs treated with SNAP (10–5 mol/L; please see the data supplement). Western blot analysis confirmed that SNAP increased the DDAH-2 protein level in a concentration-dependent manner (10–6 to 10–5 mol/L) without affecting the DDAH-1 level (Figure 2A through 2C), and the induction by 10–5 mol/L SNAP was 
4-fold compared with untreated control cells (Figure 2D). These results demonstrate that NO donors and other cGMP agonists induce DDAH-2 protein expression without affecting DDAH-1 protein expression in RAECs.
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DDAH Enzyme Activity, Methylarginines, and NO Production
Next, we determined DDAH enzyme activity by measuring the conversion of MMA and ADMA to L-citrulline. SNAP (5x10–6 to 1x10–5 mol/L) concentration dependently increased DDAH activity in RAECs at 24 hours (Figure 3A). The NO-induced DDAH activity reached its maximal level at 24 hours and declined thereafter (data not shown). 8-Bromo-cGMP (10–4 mol/L) and CNP (10–9 mol/L) significantly increased DDAH activity in RAECs (Figure 3B). Pretreatment of RAEC with KT5823 (10–6 mol/L; Figure 3C) and ODQ (5x10–6 mol/L; Figure 3D) significantly inhibited SNAP (10–5 mol/L)-induced DDAH activity. These results suggest that SNAP-induced DDAH activity in RAECs is mediated, at least in part, via induction of cGMP. We further examined the effects of higher concentrations of SNAP on intracellular DDAH enzyme activity, because direct exposure of high concentrations of NO to purified DDAH protein is known to reduce its activity in vitro. RAECs undergoing massive apoptosis after the addition of higher concentrations of SNAP (10–4 to 10–3 mol/L)20 were collected, and their intracellular DDAH enzyme activities were measured. DDAH activity was lower in RAECs undergoing apoptosis at 24 hours after exposure to 10–3 mol/L SNAP compared with control cells (5.14±0.50 versus 4.80±0.67 nmol of L-citrulline per milligram of protein; n=4).
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Significant difference at P<0.05 vs the corresponding value for SNAP alone.Subsequently, we measured the endothelial ADMA and MMA concentrations by high-performance liquid chromatography. Treatment with SNAP (10–5 mol/L) significantly reduced the intracellular ADMA and MMA contents (Figure 4A and 4B). The effects of SNAP (10–6 to 10–5 mol/L) on decreasing the MMA contents were concentration dependent and more potent than its effects on reducing the ADMA levels. However, SNAP did not significantly affect SDMA and L-arginine concentrations in RAECs (Figure 4C and 4D), suggesting that it does not affect the cell surface transmembrane cationic amino acid transporter (system y+) function that regulates transmembrane transport of SDMA, as well as ADMA and MMA.
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Next, we examined whether endothelial NO production was induced solely by treatment with cGMP agonists. As expected, the NO donors SNAP and NOR3, but not NAP, at concentrations inducing minimum apoptosis (10–5 mol/L and 2.5x10–5 mol/L, respectively), both markedly increased the NOx levels in culture supernatants from RAECs, and 8Br-cGMP (10–4 mol/L) and CNP (10–9 mol/L) also significantly increased NOx levels in the culture supernatants (Figure 5A). Pretreatment of RAECs with KT5823 (10–6 mol/L; Figure 5B) and ODQ (5x10–6 mol/L; Figure 5C) significantly inhibited the SNAP (10–5 mol/L)-induced increases in the NOx levels.
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To determine the extent of involvement of DDAH-2 in the SNAP-induced DDAH activity, we suppressed endogenous DDAH-2 mRNA using a small interfering RNA. We confirmed successful inhibition of DDAH-2 mRNA expression after transfecting RAECs with a DDAH-2–specific small interfering RNA (please see the data supplement), and this inhibition completely abrogated the SNAP-induced DDAH activity (please see the data supplement). These results indicate that DDAH-2 plays a predominant role in the SNAP-induced increase in DDAH activity.
Finally, to address the question of whether our observations are relevant to the in vivo situation, we studied the expression levels of DDAH-1 and DDAH-2 mRNA in a mouse model of chronic NO suppression. Six-week-old male C57BL/6J mice were administered an NOS inhibitor, N(G)-nitro-L-arginine methyl ester (100 mg/kg per day), for 12 weeks, resulting in reduced DDAH-2 mRNA levels in the heart and aorta, whereas DDAH-1 mRNA levels were not affected (please see the data supplement). These results demonstrate that the current findings have in vivo relevance because of the fact that endogenous NO contributes to upregulated endogenous DDAH-2.
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Discussion |
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NO is known to protect endothelial cells and increase intracellular cGMP. In the present study, low concentrations of NO donors that did not induce apoptosis increased DDAH-2 expression levels and enhanced DDAH activity in RAECs, leading to reduced levels of the endogenous NOS inhibitors ADMA and MMA. These results appear to be inconsistent with a previous report that high concentrations of the NO donor DEANONOate directly added to purified DDAH protein in vitro reversibly inhibited the DDAH enzymatic activity.17 To clarify this issue, we added high levels of NO to intact cultured RAECs to induce massive apoptosis.20 In contrast to growing RAECs, apoptotic cells that lost the ability to express genes did not show increased DDAH activity in response to NO exposure. Our results indicate that lower levels of NO induce DDAH activity via the induction of DDAH-2 gene expression in RAECs.
Of the 2 known isoforms of DDAH, DDAH-1 remains unchanged under many conditions in which vascular DDAH activity declines.5,9 On the other hand, DDAH-2 may be regulated by various factors, including low-density lipoprotein cholesterol,21 interleukin-1β,22 retinoic acid,23 and pioglitazone, a peroxisome proliferator-activated receptor-
ligand.24 In DDAH-2 transgenic mice, ADMA levels are reduced, resulting in altered tissue NO metabolism.25 Small interfering RNAs that suppress DDAH-2 expression increase endothelial ADMA and partially inhibit eNOS.26 Thus, DDAH-2, rather than DDAH-1, plays more dominant roles in modulating ADMA and MMA metabolism in vascular tissues. Our present study demonstrates specific roles for DDAH-2 in mediating NO-induced DDAH enzymatic activity and subsequent reductions in ADMA and MMA contents. A comparison of the promoter sequences upstream of the transcription start sites of the DDAH-1 and DDAH-2 genes revealed that the DDAH-2 gene contains 2 CRE-BP sites and 4 C/EBP sites implicated in cGMP-induced transcription.27 In contrast, the DDAH-1 gene has only a single CRE-BP site. NO stimulates the soluble guanylate cyclase to increase cGMP, which causes transcriptional induction probably via CRE-BP and C/EBP consensus sequences. Because generated cGMP is degraded by phosphodiesterase, cellular cGMP soon returns to baseline levels. Although the exact molecular mechanisms remain unknown, these findings may account for the distinct effects of cGMP induction on the DDAH-1 and DDAH-2 gene transcription levels.
Accumulation of the endogenous NOS inhibitors ADMA and MMA has been reported recently to reduce tissue NO production.14,28 To estimate whether the observed changes in the ADMA and MMA contents (reductions of 22% and 53%, respectively) contributed to eNOS inhibition, we used the results of regression analyses from experiments using various concentrations of authentic ADMA and MMA to obtain the eNOS activities.19 The IC50 values of ADMA and MMA for NOS obtained from rabbit thoracic aortic endothelial cells were determined to be 15.4±1.0 and 2.7±0.2 µmol/L, respectively.19 When applied to the regression lines, the baseline ADMA and MMA levels of 2.43 and 0.24 µmol/L obtained in the present study correspond with 16% and 15% inhibition of eNOS activity, respectively, whereas the ADMA and MMA levels of 1.91 and 0.12 µmol/L obtained after SNAP treatment represent 12% and 4% inhibition of eNOS activity, respectively. These data suggest that the decreased ADMA and MMA concentrations after SNAP treatment may result in significant alterations in the total eNOS activity. We reported previously that the effect of MMA on inhibiting eNOS is more potent than that of ADMA12 and that MMA contents increase during events involving endothelial dysfunction.12,28 Such altered contents of ADMA and MMA are considered to contribute to the modification of eNOS activity, thereby significantly affecting NO generation from the endothelial environment.
Although impaired DDAH activity may result in accumulation of ADMA and MMA, system y+ can also change the concentrations of L-arginine, as well as methylarginines, via alterations in transporter activity.29 In NO-generating cells, however, enhanced transporter activity not only increases the intracellular contents of ADMA and MMA, which effectively inhibit NO biosynthesis, but also that of SDMA, which is not a substrate for DDAH. In the present study, we have shown that decreases in the ADMA and MMA contents were not associated with any appreciable changes in the SDMA concentrations. Thus, decreased transmembrane transport is probably not implicated in the decreases in endogenous NOS inhibitors in endothelial cells stimulated with SNAP.
Perspectives
Vascular disease associated with hypertension, hypercholesterolemia, and diabetes is characterized by endothelial dysfunction and reduced endothelium-mediated vasodilation, whereas ADMA is implicated in the pathogenesis of atherosclerosis. Our present study suggests that local NO in the endothelial environment may be maintained under the control of a novel positive feedback loop consisting of cGMP, DDAH-2, ADMA/MMA, and eNOS (please see the data supplement). It is conceivable that, in the event of NO deprivation, other endothelium-derived cGMP agonists, such as CNP, could act as substitutes to induce DDAH-2, thereby preventing further NO loss. This positive feedback loop, therefore, represents an inherent built-in safety mechanism for endothelial cells to protect vessels against vascular damage. The exact molecular mechanism responsible for the induction of DDAH-2 by cGMP remains to be elucidated.
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Acknowledgments |
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Sources of Funding
This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas "Applied Genomics" (to M. Shichiri), Scientific Research A (to Y.H., M. Shichiri), and Scientific Research for Exploratory Research (to M. Shichiri) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid from the Smoking Research Foundation, Japan (to H.A.), and the New Drug Research Foundation, Japan (to H.A.).
Disclosures
None.
Received March 31, 2008; first decision April 21, 2008; accepted August 29, 2008.
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