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CARDIOVASCULAR
Vascular Biology Center and Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee (J.Y., R.J, Y.C., L.K.J., C.Z.); and Department of Surgery, Emory University School of Medicine, Atlanta, Georgia (J.-Z.S.)
Received March 12, 2006; accepted May 18, 2006.
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Abstract |
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). In normal vessels, eNOS is the main source of NO; however, all three isoforms are expressed in the vascular wall under pathological conditions such as atherosclerosis and restenosis after angioplasty (Wilcox et al., 1997; Banning et al., 1999; Morishita et al., 2002). There is abundant evidence that NO plays a pivotal role in protecting against the onset and progression of cardiovascular disease (Naseem, 2005), and, therefore, NO is called an endogenous antiatherogenic molecule (Ignarro and Napoli, 2005).
Reduced NO bioavailability and impaired vascular function are the key pathological characteristics of atherosclerosis-related cardiovascular diseases. Indeed, endothelial damage elicited by atherosclerosis leads to a reduction in eNOS expression with subsequent impairment of NO production (Ignarro and Napoli, 2005). In addition, scavenging of NO by reactive oxygen species (ROS), increased under atherosclerotic conditions, is also responsible for reduced NO bioavailability (Gryglewski et al., 1986). Furthermore, an endogenous NOS inhibitor as a novel mechanism involved in the impairment of NO bioavailability in atherosclerosis has recently been discovered (Boger, 2003). N
-Monomethyl-L-arginine and asymmetric dimethylarginine (ADMA) were first reported as endogenous inhibitors of NO synthase (Vallance et al., 1992); however, at that time their importance to vascular biology was unknown. Recent reports suggest that ADMA may play an important role in the pathogenesis of endothelial dysfunction and atherosclerosis (Vallance and Leiper, 2004). Identification of other potential endogenous NOS inhibitors under pathological conditions is expected and could be important in cardiovascular research (Miyazaki et al., 1999).
Reactive inflammatory mediators, formed in a variety of acute and chronic diseases such as atherosclerosis, compromise vascular function and reduce NO bioavailability (Belch, 1994; Libby, 2001). Adhesion and infiltration of leukocytes into the vessel wall are critical components of tissue injury induced under these inflammatory conditions (Frishman and Ismail, 2002; Madjid et al., 2004). Leukocyte activation initiates the assembly of cellular components of an NADPH oxidase that generates the oxidants superoxide (
) and hydrogen peroxide (H2O2). The heme protein myeloperoxidase (MPO) is another important component of leukocytes (Klebanoff, 2005). Under physiological conditions, MPO catalyzes the reaction between H2O2 and chloride that results in the production of hypochlorous acid (HOCl). MPO is the only source of HOCl in vivo. HOCl is highly reactive, reacting with amino acids and proteins to produce chloramines such as chlorotyrosine and protein derivations such as HOCl-modified low-density lipoprotein (Podrez et al., 2000). Recent reports have suggested that MPO may play an important role in atherosclerosis (Nicholls and Hazen, 2005). In this regard, MPO and HOCl-modified protein are highly expressed in both human and experimental atherosclerotic neointima (Malle et al., 2000; Hazell et al., 2001). Elevated levels of MPO are associated with the presence of coronary heart disease and predict risk in patients with acute coronary syndromes (Zhang et al., 2001b; Baldus et al., 2003).
Although the molecular mechanisms involved in MPO-mediated vascular injury are unclear, recent studies from our group and other investigators suggest that the MPO-mediated negative effect on NO signaling and the resulting endothelial dysfunction may be an important mechanism (Eiserich et al., 2002; Zhang et al., 2003). We have recently found that both purified HOCl and HOCl produced from activated leukocytes can react very rapidly with the NOS substrate L-arginine to produce chlorinated L-arginine (cl-L-Arg) (Zhang et al., 2001a). Interestingly, cl-L-Arg potently inhibited NO metabolites in the medium of cultured endothelial cells and impaired endothelial function at the tissue level. The results suggest that inflammation-derived cl-L-Arg might be a novel endogenous inhibitor of NO bioavailability. However, two important unanswered issues remain. First, is the cl-L-Arg-mediated reduction of NO bioavailability a result of direct inhibition of NOS? Second, if the answer to the first question is "yes," is the inhibitory effect on NOS isoforms selective or nonselective? We therefore designed the current study to determine the inhibitory effect of cl-L-Arg on recombinant NOS isoforms. Our results suggest that cl-L-Arg is a potent inhibitor of NOS, and the inhibitory effect on NOS isoforms is nonselective. The nonselective inhibitory effect functionally decreases NOS isoform-mediated vessel reactivity and signaling molecule cGMP. Inflammation-derived cl-L-Arg might be a novel endogenous inhibitor of NOS.
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Materials and Methods |
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nitro-L-arginine methyl ester (L-NAME), and the NOS assay kit were purchased from Calbiochem (San Diego, CA). The cGMP enzyme immunoassay kit and 3H-labeled L-arginine were from Amersham. Cl-L-Arg was freshly prepared by incubating L-arginine with an equimolar concentration of HOCl as described previously (Zhang et al., 2001a). All of the other materials were purchased from Sigma Chemical (St. Louis, MO). Animals. Ten-week-old male Sprague-Dawley rats were obtained from Harlan Breeding Laboratories (Indianapolis, IN). All rats were maintained at a constant humidity (60 ± 5%), temperature (24 ± 1°C), and light cycle (6:00 AM–6:00 PM) and were fed a standard rat pellet diet (Ralston Purina Diet) ad libitum. The animals were anesthetized with ketamine (80 mg/kg)-xylazine (5 mg/kg). All protocols were approved by the Institutional Animal Care and Use Committee at the University of Tennessee and were consistent with the Principles of Laboratory Animal Care (National Institutes of Health publication 85-23, revised 1985).
Recombinant NOS Activity Assay. Using the NOS radioactive assay kit from Calbiochem, we determined NOS activity by monitoring the conversion of [3H]L-arginine to [3H]L-citrulline by the three recombinant NOS isoforms. In brief, 1 µCi/ml 3H-labeled L-arginine and cl-L-Arg (0–500 µM) were added to reaction solutions containing nNOS, iNOS, or eNOS (
5 µg). L-NAME (1 mM) was added as a positive control. After a 30-min incubation, the reaction was stopped. Reaction samples were then incubated with ion exchange resin, and the resin-bound [3H]L-arginine and the neutrally charged [3H]L-citrulline were separated by centrifuge. The radioactivity of newly formed [3H]L-citrulline was determined by scintillation counting, and IC50 values were calculated from concentration-response curves.
eNOS-Mediated Vasodilation and cGMP Levels in Vascular Tissue Acetylcholine (ACh)-induced vascular relaxation of precontracted intact arteries is mediated by activation of eNOS in endothelial cells, followed by an increase in cGMP level in vascular smooth muscle cells. To test the effect of cl-L-Arg on eNOS activity at the tissue level, the ACh-induced relaxation in rat intact aortic rings was determined in the absence or presence of cl-L-Arg by using the method described previously with some modification (Zhang et al., 2001a, 2003). In brief, rat aortic arteries were isolated and cut into individual ring segments (3 mm wide). The rings were suspended from a force-displacement transducer in a tissue bath. Ring segments were bathed in Krebs-Henseleit buffer (KH), which was maintained at 37°C and aerated with 95% O2-5% CO2. A passive load of 2 g was applied to all ring segments and maintained at this level throughout the experiment. Before the start of the experiment, the ring segments were allowed to equilibrate for 1 h with 5 µM indomethacin to block cyclooxygenase-derived contribution to vasodilation (i.e., prostacyclin). In subsequent experiments, vessels were submaximally contracted (50% of KCl response) with phenylephrine (PE) (30–100 nM). When tension development reached a plateau, ACh (1 nM to 30 µM) was added cumulatively to the bath to evoke endothelium-dependent relaxation. Twenty minutes before the addition of PE, either cl-L-Arg (1 nM to 100 µM) or vehicle (KH) was added into the tissue bath. In some vessels, L-NAME (100 µM) was added as a positive control. It should be noted that we increased the dose range [from 0 to 10 µM (Zhang et al., 2001a) to 0 to 100 µM] based on the effect of cl-L-Arg on the recombinant NOS. In addition, consistent with the NOS activity measurement, the incubation time was 20 min before PE (30 min before ACh) in the current study instead of 60 min before PE (70 min before ACh) in our previous report (Zhang et al., 2001a). The vessels were collected at the basal condition (without any reagents) and after adding the maximal dose of ACh for cGMP measurements to confirm the effect of cl-L-Arg on downstream effectors of NO.
iNOS-Mediated Attenuation of Vascular Contraction and cGMP Levels in Vascular Tissue. In normal rat arteries, iNOS is not expressed. However, iNOS is highly expressed in arteries from lipopolysaccharide (LPS)-injected rats. Therefore, endothelium-denuded aortic artery isolated from LPS-injected rats provides a good model for studying iNOS in the vascular wall (Griffiths et al., 1995). In this experiment, rats were administered a single i.p. injection of LPS (5 mg/kg in 1.5 ml of saline), and other rats were injected with the same volume of saline only, thereby serving as the control group. The animals were sacrificed 12 h after their respective injections. It should be noted that for the iNOS stimulation and vascular hyporesponsiveness, 5 to 20 mg/kg i.p. were used for the rats described in previous publications. Our unpublished data demonstrated that, 12 h after injection of LPS, the dose of 5 mg/kg i.p. was able to increase MPO activity, stimulate iNOS activity, and induce stable vascular dysfunction (hyporesponsiveness to PE). We thus selected 5 mg/kg i.p. as our experimental dose and 12 h after injection as our experimental time point. The aortas were isolated and cut into ring segments (3 mm wide). The endothelium was then removed mechanically by gently rubbing the luminal surface of the segments with a thin wooden stick. The rings were suspended from a force-displacement transducer in a tissue bath with KH. The successful denudation of endothelium was confirmed by the lack of the relaxation response to ACh. The vessels were incubated with either cl-L-Arg (1 nM to 100 µM) or vehicle (KH), followed by cumulatively adding PE (1 nM to 30 µM) to elicit the dose-response curve. The vessels incubated with either cl-L-Arg or vehicle were collected for cGMP analysis.
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). Under the experimental condition, EFS elicits vascular contraction and stimulates NO release by nNOS. In this experiment, the mesenteric arteries were isolated and cut into ring segments (3 mm wide). The endothelium was then removed mechanically by gently rubbing the luminal surface of the segments with a thin wooden stick to avoid any interaction via eNOS. The rings were suspended from a force-displacement transducer in a tissue bath with KH. A passive load of 1.0 g was applied to all ring segments and maintained at this level throughout the experiment. For EFS experiments, segments were mounted between two platinum electrodes 0.5 cm apart and connected to a stimulator. The vessels were treated with either vehicle (KH) or cl-L-Arg (1 nM to 100 µM) for 20 min, followed by frequency-response to EFS (1, 2, 4, 8, and 16 Hz). Some vessels were treated with L-NAME (100 µM) as a positive control group. After stimulation with EFS, vessel segments were collected for cGMP analysis.
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). Unstimulated and agonist-stimulated artery segments were snap-frozen in liquid nitrogen and stored at –80°C. Measurement of tissue cGMP was performed with a cGMP enzyme immunoassay kit (Amersham), according to the manufacturer's recommendation. Values for cGMP were standardized by tissue protein (milligrams). Statistical Analysis. All data are presented as means ± S.E. Dose-response profiles for different experimental conditions were analyzed and tested to determine differences in relaxation responses using the SigmaStat statistical analysis program. Unpaired observations were assessed by analysis of variance and the Student-Newman-Keuls post hoc test. A value of P < 0.05 was regarded as significant. All statistical analysis was done with SPSS software.
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Results |
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3 to 5 µM. No difference was found among their IC50 values (P > 0.05) (Fig. 1B). Cl-L-Arg Inhibits eNOS-Mediated Vessel Relaxation and eNOS-Elicited cGMP at the Tissue Level. ACh-induced vessel relaxation of endothelium intact arteries is mediated by eNOS in the endothelium and its signaling messenger, cGMP, in vascular smooth muscle cells. As shown in Fig. 2A, ACh elicited a dose-dependent relaxation in isolated rat aortic rings precontracted by PE. However, the ACh-induced vasodilatation was inhibited by cl-L-Arg in a dose-dependent manner. Consistent with the vasodilation, cl-L-Arg potently inhibited the eNOS-mediated increase of cGMP in the vascular wall (Fig. 2B).
Cl-L-Arg Inhibits iNOS-Mediated Attenuation of Vascular Contraction and cGMP Levels in Vascular Tissue. iNOS is responsible for the decreased contractile response to PE in endothelium-denuded vessels from LPS-injected animals. Consistent with previous studies (Griffiths et al., 1995), the contractile response to PE was significantly attenuated in aortic rings from LPS-injected animals (Fig. 3A). In the presence of cl-L-Arg, the attenuated response to PE was restored, and the effect was concentration dependent (Fig. 3B). Cl-L-Arg-mediated improvement of vascular contraction accompanied the inhibition of the signaling molecule of NO, cGMP, in the vascular wall (Fig. 3C).
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). In the presence of cl-L-Arg, the EFS-mediated contractile response was significantly increased (Fig. 4A). Cl-L-Arg-mediated augmentation of vascular contraction accompanied the inhibition of the signaling molecule of NO, cGMP, in the vascular wall (Fig. 4B).
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Discussion |
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; Salerno et al., 2002). In fact, most NOS inhibitors currently in use are structural variants of L-arginine. Our study demonstrated that MPO-derived HOCl is able to react with L-arginine, resulting in the rapid formation of chlorinated L-arginine, cl-L-Arg (Zhang et al., 2001a). Analysis with mass spectrometry (MS) confirmed that the 
-amino and guanidino nitrogens of L-arginine are sites of HOCl-dependent chlorination (Zhang et al., 2001a). In cultured endothelial cells, we found that cl-L-Arg is a potent inhibitor of the formation of the NO metabolites nitrate (
) and nitrite (
). However, it is unknown whether the reduced NO metabolites are mediated by a direct inhibitory effect on eNOS or by other effects that include a nonspecific scavenger effect or an increase in the production of ROS. In addition, if the effect is mediated by direct inhibition of eNOS, what is the effect of cl-L-Arg on other NOS isoforms? Using recombinant NOS, we found that cl-L-Arg had a direct inhibitory effect on the activity of NOS. Furthermore, the NOS inhibitory effect of cl-L-Arg on NOS isoforms is nonselective, as all three NOS isoforms were inhibited with a similar IC50. To test the potential inhibitory effect of cl-L-Arg on the three NOS isoforms in tissue, we determined the effect of cl-L-Arg on eNOS-, iNOS-, and nNOS-mediated vessel reactivity, as well as the NOS signal molecule cGMP in the vessels. Our results suggest that cl-L-Arg potently inhibited the effects of all three NOS isoforms on vessel reactivity as well as the NOS signal molecule cGMP. Thus, the nonselective inhibitory effect of cl-L-Arg on NOS was confirmed at the tissue level.
Although many NOS inhibitors have been identified, most of them are exogenous (Alderton et al., 2001; Salerno et al., 2002). Endogenous NOS inhibitor as a novel mechanism involved in the impairment of NO bioavailability in atherosclerosis has been recently discovered (Miyazaki et al., 1999; Boger, 2003). In this regard, ADMA is a representative example (Boger, 2004; Vallance and Leiper, 2004). ADMA is released when methylated proteins are degraded into their amino acid components during hydrolytic protein turnover (Boger, 2003). Accumulating evidence from animal studies and prospective clinical studies suggests that elevated plasma or serum levels of ADMA are associated with reduced NO bioavailability, endothelial dysfunction, and the development of cardiovascular diseases (Boger, 2003).
It is well established that inflammation is an important factor in the development of atherosclerosis and many other diseases. Leukocyte activation is a key cellular event involved in inflammation-related diseases. This study demonstrated that cl-L-Arg, an endogenous variant of L-arginine produced by leukocyte-derived MPO, had a potent inhibitory effect on NOS. Cl-L-Arg might serve as a novel endogenous nonselective NOS inhibitor under inflammatory conditions.
Inflammation is a complex process. Although it is unclear why inflammatory products such as cl-L-Arg inhibit something such as iNOS that is induced specifically for inflammation, this phenomenon can also occur in other inflammatory processes such as restenosis after angioplasty, in which both proproliferative signal molecules and antiproliferative signal molecules exist concurrently. The homeostasis system may balance the inflammatory and anti-inflammatory mediators, avoid damage due to the overproduction of some specific inflammatory mediators, and/or influence the recovery from inflammation. With respect to cl-L-Arg, although it is able to inhibit overproduction of NO via iNOS during sepsis condition, cl-L-Arg may also be an important damage mediator to endothelial function.
It has been estimated that during moderate inflammation the concentration of HOCl within the extracellular space can reach as high as 340 µM (Katrantzis et al., 1991). Both in vitro and in vivo studies have confirmed that L-arginine is an important target for HOCl (Hazen et al., 1997; Carr et al., 2000; Winterbourn and Kettle, 2000). However, the accurate circulating, tissue, and cellular levels of cl-L-Arg under these pathological conditions are currently unknown because of the lack of a sensitive and specific method for determining the concentration of cl-L-Arg. This is the major limitation for the current study. As the absolute rate constant for the reaction of HOCl with arginine is similar to that with tyrosine (Pattison and Davies, 2001), quantitation of 3-chlorotyrosine by liquid chromatography-mass spectrometry might be an alternative method to reflect the levels of cl-L-Arg. Another limitation is that cl-L-Arg might also be highly reactive. Therefore, the stability of this modified L-arginine in vivo may not be as good as that of ADMA. However, continued production of cl-L-Arg under inflammatory conditions should have significant biological effects. The in vivo role of cl-L-Arg in the development of cardiovascular diseases will need to be studied in the future.
In conclusion, L-arginine chlorination results in the formation of a nonselective NOS inhibitor, cl-L-Arg. cl-L-Arg may serve as a novel endogenous NOS inhibitor and an important mediator in vascular dysfunction under inflammatory conditions such as atherosclerosis. Blocking cl-L-Arg formation might be a new therapeutic approach to cardiovascular diseases.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: NO, nitric oxide; NOS, nitric-oxide synthase; nNOS, neuronal nitric-oxide synthase; iNOS, inducible nitric-oxide synthase; eNOS, endothelial nitric-oxide synthase; ROS, reactive oxygen species; ADMA, asymmetric dimethylarginine; MPO, myeloperoxidase; HOCl, hypochlorous acid; L-NAME, N-nitro-L-arginine methyl ester; cl-L-Arg, chlorinated L-arginine; ACh, acetylcholine; KH, Krebs-Henseleit; PE, phenylephrine; LPS, lipopolysaccharide; EFS, electrical field stimulation.
Address correspondence to: Dr. Chunxiang Zhang, Vascular Injury Laboratory, Vascular Biology Center and Department of Surgery, University of Tennessee Health Science Center, 956 Court Ave., Coleman Bldg., H300, Memphis, TN 38163. E-mail: czhang{at}utmem.edu
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