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From the Department of Pathophysiology, Semmelweis University, Budapest, Hungary; and the Department of Physiology, New York Medical College, Valhalla, New York
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Abstract |
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145 µm) isolated from control rats and rats with methionine diet-induced HHcy were investigated by videomicroscopy. Increases in intraluminal flow (from 0 to 40 µl/min) elicited dilations of control vessels (maximum, 25 ± 2 µm), responses that were absent in HHcy arteries. The nitric oxide (NO) synthase inhibitor L-NAME inhibited flow-induced dilation of control coronaries, whereas it had no effect on responses of HHcy arteries. Dilations of control and HHcy arteries to the NO donor sodium nitroprusside were not different. Responses to flow in HHcy coronary arteries were unaffected by administration of L-arginine or the prostaglandin H2/thromboxane A2 receptor antagonist SQ 29,548. However, in the presence of superoxide dismutase (plus catalase) or the superoxide scavenger Tiron increases in flow elicited L-NAME-sensitive dilations of HHcy coronaries (maximum, 18 ± 5 µm). Also, superoxide dismutase significantly reduced the enhanced superoxide production of HHcy coronaries (measured by the lucigenin chemiluminescence method). Single vessel Western blotting showed an increased tyrosine nitrosation (a stable biomarker of tissue peroxynitrite formation) in HHcy coronaries. Also, extensive prevalence of 3-nitrotyrosine immunoreactivity was observed in HHcy coronaries that was confined primarily to the subendothelial layers of smooth muscle. We propose that in HHcy an increased level of superoxide scavenges NO forming peroxynitrite, which increases protein nitrosation. The reduced bioavailability of NO impairs flow-induced dilations of coronary arteries, which may contribute to the development of coronary atherosclerosis and ischemic heart disease.
One of the mechanisms by which HHcy elicits its adverse vascular effects is by altering endothelial function. Recent studies have shown that even mild HHcy (15 to 30 µmol/L) is associated with significant impairment of endothelium-dependent vasoactive responses in large arteries and aorta of monkeys5 and mice,6 as well as in rat skeletal muscle arterioles.7-9 Despite this compelling evidence, there is little data regarding HHcy-induced alterations in the coronary circulation, where potential HHcy-induced pathology could contribute greatly to fatal cardiac events.
Flow-induced dilation of small coronary vessels is one of the most important mechanisms contributing to the local regulation of myocardial blood flow, is a response that is mediated by endothelium-derived nitric oxide (NO) in most species.10,11 Because NO exerts both vasodilatory and anti-aggregatory actions, the impairment of flow-induced NO release likely leads to ischemic episodes and contributes to the development of coronary heart disease. Indeed, it has been shown that pathological conditions that are associated with an increased risk of coronary heart disease, such as arteriosclerosis, diabetes, and hypertension are characterized by a decreased NO synthesis/release interfering with endothelium-dependent regulation of coronary circulation.12
HHcy may affect endothelial function of coronary vessels via mechanisms that increase oxidative stress, as suggested by recent studies on endothelial cells in culture.13,14
Indeed, previous studies have demonstrated that enhanced oxidative stress impairs endothelial functions in hypercholesterolemia, diabetes, and hypertension.15
One of the key reactive oxygen metabolites is superoxide (O2
), which interacts with NO and generates peroxynitrite (ONOO-).16
It could be hypothesized that NO-mediated flow-induced coronary dilation is impaired because of an enhanced generation of superoxide in HHcy, which scavenges NO (released to increases in flow) forming ONOO-. This mechanism may contribute to the development of coronary heart disease in HHcy.
To test this hypothetical mechanism we investigated flow-induced responses in isolated small intramural coronary arteries of HHcy rats in the presence and absence of pharmacological probes of known action on synthesis of endothelial factors and metabolism of superoxide. Furthermore, increased in vivo generation of ONOO- in HHcy coronary arteries was evidenced by detecting protein tyrosine nitrosation (a stable biomarker of tissue ONOO- formation)16-19 with single vessel Western blotting and immunohistochemistry.
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Materials and Methods |
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Isolation of Intramural Coronary Arteries and Videomicroscopy
Experiments were conducted on isolated small intramural coronary arteries (diameter, 145 µm), as described previously.7-9,12
In brief, the heart was excised, the septum was exposed, and a branch 1.5 mm in length of the septal coronary artery running intramuscularly was isolated. The arteriole was cannulated on both sides in an organ chamber containing physiological salt solution (in mmol/L: 110 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 5.0 glucose, and 24.0 NaHCO3, equilibrated with 10% O2, 5% CO2, 85% N2, at pH 7.4, 37°C). Pressure on both sides was adjusted by a pressure servo-control system. Internal diameter at the midpoint of the arterial segment was measured with videomicroscopy. Intraluminal flow was established at a constant intravascular pressure (80 mmHg) by changing the inflow and outflow pressure to an equal degree, but in opposite directions, to keep midpoint intraluminal pressure constant9
and was measured with a ball flowmeter (Omega Engineering Inc.).
Functional Studies
After the equilibration period changes in diameter of isolated coronaries were assessed in response to step increases in intraluminal flow (from 0 to 50 µl/min). Then the vessels were exposed in various protocols to incubation with N
-nitro-L-arginine-methyl-ester (L-NAME) (3 x 10-4 mol/L, eNOS inhibitor) or extracellular L-arginine (10-4 mol/L, the substrate of eNOS) or SQ 29,548 (10-6 mol/L for 20 minutes, a TxA2/PGH2 receptor inhibitor), or the free radical scavengers Tiron (4,5-dihydroxy-1,3-benzene-disulphonic acid, 10 mmol/L, a spin trap known to eliminate superoxide in coronary endothelium20
), or superoxide dismutase (SOD) (120 U/ml for 30 minutes, a potent scavenger of superoxide in coronary arteries20
and isolated arterioles21
) plus catalase (CAT) (80 U/ml, for 30 minutes, to eliminate H2O2 formed by SOD)21
or SOD plus L-NAME or the ONOO- scavenger urate16
(10-4 mol/L for 30 minutes) and flow-induced responses were obtained again. Flow (40 µl/min)-induced responses of HHcy arteries were also assessed before and after administration of aminoguanidine (10-3 mol/L, an iNOS inhibitor), indomethacin (3 x 10-5 mol/L, a COX inhibitor), diphenyliodonium [10-4 mol/L, abluminally, an inhibitor of flavin-containing enzymes, including NAD(P)H oxidases] or dithiothreitol (10-3 mol/L, a thiol-reducing agent thought to reverse ONOO--induced cysteine oxidation22
). Arteriolar responses to the NO donor sodium nitroprusside (10-9 to 10-6 mol/L) were also assessed. In separate experiments responses of control arterioles to increasing concentrations of authentic ONOO- were also obtained in the presence and absence of uric acid. In other experiments flow-induced responses of control arteries were obtained, then the vessels were incubated with authentic ONOO- (nominal final concentration, 10 µmol/L) for 20 minutes followed by a 10-minute washout and flow-induced responses were obtained again.
At the conclusion of each experiment to obtain the maximum passive diameter, the suffusion solution was changed to a Ca2+-free solution, which contained EGTA (ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid, 10-3 mol/L), the vessel was incubated for 10 minutes and changes in passive arteriolar diameter in response to changes in intraluminal pressure (20 to 140 mmHg) were obtained.
Measurement of Vascular Superoxide Level
Vascular O2- production was assessed by the lucigenin chemiluminescence method6 in collaboration with Dr. Pavel Kaminski and Dr. Michael S. Wolin according to the modified protocol of Mohazzab and colleagues.23 In brief, coronary arteries were isolated from control (n = 8) and HHcy (n = 8) rats. Vessels from each animal were pooled and placed in scintillation vials containing 1 ml of physiological buffer solution and 10 µmol/L of lucigenin. Lucigenin chemiluminescence was measured in a liquid scintillation counter (Mark V; TmAnalytic, Elk Grove Village, IL) with a single active photomultiplier tube positioned in out-of-coincidence mode in the darkroom. Scintillation counts were obtained 15 to 20 minutes after addition of vessels (averaged) in the absence or presence of SOD and background-corrected values were normalized to tissue weight. In separate experiments O2- production by control coronary arteries and vessels preincubated with authentic ONOO- (nominal final concentration, 10 µmol/L for 20 minutes) were compared.
Materials
Authentic ONOO- was obtained from Calbiochem (La Jolla, CA) as an aqueous stock solution in 4.7% NaOH (nominal concentration, 200 mmol/L) and was stored aliquoted at -80°C under inert gas, and protected from light throughout the experiments. Immediately before each experiment, an aliquot of the stock solution was diluted into an ice-cold alkaline solution24
from which an appropriate volume was administered immediately in the organ bath. In Figure 2
the amount of ONOO- administered to a 10-ml bath solution is expressed. SQ 29,548 (Cayman Chemicals, Ann Arbor, MI) was dissolved in ethanol and urate (Calbiochem) was dissolved in alkaline buffer. All other salts and chemicals were obtained from Sigma-Aldrich Co. and solutions were prepared on the day of the experiment. All drugs were added to the vessel chamber, and final concentrations are reported.
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Single small coronary arteries from the same control and HHcy rats that were used for functional studies were isolated, snap-frozen in liquid nitrogen, and stored at -80°C. Isolated coronary arteries of control rats incubated with authentic ONOO- (nominal concentration, 10 µmol/L) served as positive controls. Samples were homogenized by sonification in Laemmli buffer, boiled for 5 minutes, and loaded onto a 10% acrylamide gel (Criterion Gels; Bio-Rad, Richmond, CA), resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transferred to Hybond P (Amersham Life Science, Arlington Heights, IL) membrane at 1 mA/cm2 for 60 minutes with a semi-dry blotting system (Bio-Rad). The membranes were blocked in Tris-buffered saline-Tween 20 (TBST) buffer containing 5% nonfat milk for overnight at 4°C. Primary polyclonal anti-3-nitrotyrosine antibody (1:750; Cell Signaling Technology Co., Beverly, MA) or monoclonal anti-GAPDH antibody (1:2500; Chemicon Co.) was added to the membrane for 1 hour at room temperature. The membranes were washed with phosphate-buffered saline (PBS) and incubated for 1 hour with sheep anti-rabbit IgG-horseradish peroxidase or donkey anti-mouse IgG-horseradish peroxidase (Amersham) at the final titer of 1:4000. The membranes were developed with ECL-Plus (Amersham) and analyzed with densitometry. Anti-GAPDH was used to normalize for loading variations. In separate bioassay experiments arteries of control rats were incubated with ONOO- in the absence and presence of urate (10-4 mol/L) and 3-nitrotyrosine content was detected.
Immunohistochemical Detection of 3-Nitrotyrosine
Tissue samples from the interventricular septum were embedded in OTC 4583 medium (Sakura Finetek, Torrance, CA), snap-frozen in liquid nitrogen, and immunolabeling was performed according to the modified protocol of Baker and colleagues19 and others.17,18,25 Tissue sections (thickness, 4 µm) were cut by using a cryostat and collected on Probe-on-Plus (Fisher Scientific, Pittsburgh, PA) microscope slides. Sections were fixed with cold (4°C) acetone and exposed to 3% hydrogen peroxide (5 minutes, 25°C, in methanol) to quench endogenous peroxidase activity. Slides were washed three times for 5 minutes with PBS. To block nonspecific binding of antibodies, sections were incubated for 4 hours (25°C) with 2.5% normal horse serum, which was then aspirated from each section. Then sections were incubated overnight at 4°C with optimally diluted (in PBS containing 0.1% bovine serum albumin and 0.2% Triton X-100) primary antibody against nitrated tyrosine residues of proteins (1:100; Cell Signaling Technology Co.). To label bound primary antibody, sections were incubated for 45 minutes at 25°C with a 1:100 dilution of goat anti-rabbit secondary antibody conjugated to biotin (Vector Laboratories, Burlingame, CA). Between each step of labeling protocol sections were rinsed in 0.1% Triton X-100 in 0.05 mol/L of Tris-saline solution. Sections were then incubated with avidin-biotinylated enzyme complex (ABC Vectastain, Vector Laboratories), stained with Vector-DAB (diaminobenzidine tetrahydrochloride) substrate and counterstained with hematoxylin. Some samples were stained with Vector-VIP substrate to increase specificity and counterstained with methyl green. Sections were then rinsed in distilled water, permanently mounted with VectaMount medium, and covered with a coverslip. The specificity of the immunolabeling was evaluated by omitting the primary antibody or omitting both primary and secondary antibodies in control experiments. Further specificity controls were made by immunostaining sections after overnight incubation of the primary antibody with the homologous antigen for 3-nitrotyrosine (10 mmol/L). Images of the sections were collected with a CoolSnap-CF CCD camera (Roper Scientific, Tucson, AZ) connected to an Olympus BX60 microscope.
Data Analysis
Dilation of isolated arteries were expressed as absolute values. Statistical analyses were performed by two-way analysis of variance for repeated measures followed by the Tukey post hoc test or Student’s t-test, as appropriate. P < 0.05 was considered statistically significant. Data are expressed as means ± SEM.
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Results |
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Flow- and Agonist-Induced Dilations of Coronary Arteries
Stepwise increases in intraluminal flow elicited significant dilations in isolated coronary arteries of control rats, responses that were inhibited by L-NAME (Figure 1, A and B)
. In contrast, in coronary arteries of HHcy rats flow-induced responses were essentially absent both in the presence and absence of L-NAME (Figure 1, A and B)
. Dilations to cumulative doses of sodium nitroprusside were not significantly different between control and HHcy arteries (Figure 1C)
. Flow-induced responses of HHcyarteries were not affected by the presence of excess extracellular L-arginine (10-4 mol/L) or by administration of the PGH2/TxA2 receptor antagonist SQ 29,548 (10-6 mol/L, Figure 2C
).
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, but did not affect flow-induced dilations of control arteries (Figure 2A)
. In the presence of SOD (plus catalase) flow-induced dilations of HHcy arteries were abolished by L-NAME (maximum, 5 ± 3 µm). The structurally different superoxide scavenger Tiron also restored flow-induced dilations of HHcy arteries (Figure 2C)
that were inhibited by L-NAME (maximum, 6 ± 4 µm). Uric acid, a potent ONOO- scavenger,16
had no effect on flow-induced responses of HHcy arteries (Figure 2C)
. Flow-induced responses of HHcy arteries were augmented by abluminal application of diphenyliodonium, but were unaffected by aminoguanidine, indomethacin, or dithiothreitol (Figure 2D)
. Administration of dithiothreitol elicited an 10-µm dilation that was followed by a gradual 15-µm constriction. Vasoactive Effects of ONOO-
Low doses of authentic ONOO- (10-8 to 10-4 mmol ONOO- administered to 10 ml bath solution; corresponding to calculated nominal final concentrations: 10-9 to 10-5 mol/L, although actual effective concentrations are likely to be lower because of the short half-life of ONOO- at physiological pH) did not have significant vasoactive effects, whereas ONOO- at high doses elicited slight, but significant, constrictions of coronary arteries of control rats that were completely abolished by uric acid (Figure 2E)
. Decomposed ONOO- (ONOO- was incubated for 30 minutes in Kreb’s solution at 37°C), unlike acute administration of authentic ONOO-, did not elicit vasoactive effects (not shown). Flow-induced dilations of control coronary arteries were not affected significantly by pretreatment with ONOO- (Figure 2F)
.
Vascular Superoxide Level in Coronary Arteries
Under baseline conditions, levels of O2- produced by coronary arteries of HHcy rats were significantly higher (by 4-fold) than in vessels of control rats (as detected by lucigenin-enhanced chemiluminescence; Table 1
). Treatment with SOD significantly decreased superoxide levels in control and HHcy arteries eliminating the difference between the groups (Table 1)
. Preincubation of control coronary arteries with authentic ONOO- had no significant effect on vascular O2- production (control, 100 ± 25%; control + ONOO-, 128 ± 23%; n = 4 in each group, data are normalized to control mean).
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Western blot analysis of coronary artery lysates showed an extensive prevalence of nitrated tyrosine residues of proteins in HHcy coronaries, whereas 3-nitrotyrosine immunoreactivity was weak in control vessels (a Western blot representative to three separate experiments is shown in Figure 3A
). In control arteries pretreated with authentic ONOO- (Figure 3A
, lanes 1 and 2) there was a strong 3-nitrotyrosine immunoreactivity that had a similar pattern as the 3-nitrotyrosine immunoreactivity found in HHcy coronaries. Figure 3B
shows the summary data of the total background-corrected band densities normalized to the arterial GAPDH content indicating that 3-nitrotyrosine content of HHcy coronaries was significantly increased, as compared to vessels of control rats (Figure 3B)
. In separate experiments we showed that acute formation of 3-nitrotyrosine by pretreatment of control arteries with ONOO- can be prevented by the ONOO- scavenger urate (Figure 3C)
. Administration of decomposed ONOO- did not result in detectable 3-nitrotyrosine immunoreactivity.
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Samples from the hearts of four HHcy animals were analyzed with immunohistochemistry. In large intramural coronary arteries of HHcy rats immunostaining for nitrotyrosine was localized mainly to the subendothelial layers of the media (Figure 4A)
, whereas the endothelium was relatively free from immunoreactivity (inset, arrow). Similar subendothelial localization of 3-nitrotyrosine immunoreactivity was found in large (Figure 4C)
and small intramural coronary arteries and arterioles (Figure 4D)
, whereas the endothelium of these vessels was also relatively free from 3-nitrotyrosine immunoreactivity (Figure 4D)
. Immunostaining for 3-nitrotyrosine also could not be detected in the myocardium. In control experiments on consecutive tissue sections in the absence of the primary antibody or both primary and secondary antibodies or after absorption of the primary antibody with the homologous antigen for 3-nitrotyrosine (Figure 4, B and F)
there was no evidence for nonspecific immunostaining.
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Discussion |
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To elucidate the effect of HHcy on endothelial regulation of coronary resistance vessels first we demonstrated that under control conditions increases in flow elicit substantial dilations of small coronary arteries, a response that primarily depends on the endothelial release of NO (Figure 1)
.10,11
In contrast, flow-induced responses were essentially eliminated in coronary arteries isolated from rats with diet-induced chronic (4 weeks) HHcy (Figure 1)
. The finding that neither L-NAME nor the TxA2 receptor inhibitor SQ 29,548 affected the lack of dilation of HHcy coronaries suggest that it is most likely because of an impaired NO mediation9
(Figures 1 and 2)
. These findings have important clinical applications, because in humans a similar degree of mild HHcy, either chronic or transient after an experimental methionine load, is also associated with an impaired dilation of peripheral arteries in response to infusion of ACh and/or to a release of an occlusion.26-28
Thus, it is likely that HHcy impairs NO mediation of flow-induced dilation and thereby limits myocardial blood flow and promotes platelet aggregation and/or imposes greater demand on other compensatory mechanisms and may lead to ischemic heart disease. Because dilation of HHcy coronary arteries to the NO donor sodium nitroprusside were normal (Figure 1C)
, it is likely that the dilator capacity of the smooth muscle is unaffected by 4-week HHcy.
The finding, that scavenging of reactive oxygen species with SOD, which had no significant effect on responses of control coronaries (Figure 2A)
, restored flow-induced dilation in arteries of HHcy rats (Figure 2B)
suggests that in HHcy arteries increases in flow do elicit NO synthesis, but an increased production of reactive oxygen species, predominantly superoxide, inactivates the released NO. This idea is further supported by the findings that Tiron, a structurally different cell-permeable superoxide scavenger also effectively restored flow-induced dilations of HHcy coronary arteries (Figure 2C)
. An increased superoxide production in HHcy coronaries was also evidenced by the significantly increased lucigenin chemiluminescence in these vessels (Table 1)
, corresponding well with similar findings in the aorta of mice with genetic HHcy suggesting that increased superoxide production is independent from the model of HHcy.6
Because in the present study the increased lucigenin chemiluminescence was substantially inhibited by SOD (Table 1)
it is likely that HHcy is primarily associated with an increased extracellular production of superoxide in the coronary arteries. An important in vivo role for increased superoxide production in HHcy is supported by observations that endothelial function in humans with high homocysteine plasma concentrations can be improved by oral administration of antioxidants (eg, vitamin E, vitamin C).29,30
Because flow-induced responses of HHcy coronary arteries were significantly augmented by diphenyliodonium, it is likely that an increased activity of vascular NAD(P)H oxidase,23
rather than iNOS31
or cyclooxygenase,8
contributes to superoxide production in HHcy coronary arteries (Figure 2D)
. In addition, HHcy may also alter cellular redox state by activating xanthine oxidase32
and/or down-regulating the expression of glutathione peroxidase.33
Because administration of L-arginine did not restore flow-induced dilations in HHcy coronaries (Figure 2C)
, it is unlikely that HHcy-induced endothelial dysfunction is due to reduced L-arginine availability.
It is known that interaction of superoxide with NO in vitro results in the formation of ONOO-.16,34
Because single vessel Western blotting revealed that in coronary arteries of HHcy rats there is an increased protein 3-nitrotyrosine content (a stable reaction product of ONOO-;16-19
Figure 3
), it is likely that in chronic HHcy an increased level of superoxide scavenges NO released to the constant presence of coronary blood flow resulting in increased formation of ONOO- in vivo. Further evidence for ONOO- formation in HHcy is also provided by studies showing 3-nitrotyrosine staining in the aorta of mice with genetic HHcy6
and by studies on endothelial cells in culture showing inactivation of NO by superoxide and generation of ONOO- induced by high concentrations of homocysteine.35
In the present study we found that protein tyrosine nitrosation in HHcy arteries is predominantly confined to the subendothelial smooth muscle layer of the arterial wall (as shown with immunohistochemistry, Figure 3
), raising the possibility that smooth muscle cells in this region are significant sources for production of superoxide and ONOO-. Indeed, previous studies showed that NAD(P)H oxidase expressed in the smooth muscle cells is a major source of O2-.23,36,37
It is of note that a similar pattern of immunostaining for 3-nitrotyrosine was observed both in large and small coronary arteries and arterioles (Figure 4; D and E)
, suggesting that adverse effects of HHcy, similar to hypercholesterolemia,12
extend into the coronary microcirculation.
The pathological role of ONOO- is likely to be multifaceted. Although acute administration of high doses of exogenous ONOO- may elicit vasoconstriction in vitro24,38
(Figure 2E)
flow-induced responses were not affected by the potent ONOO- scavenger uric acid16
in coronary arteries of HHcy rats (Figure 2C
and Figure 3C
) suggesting that ONOO- does not act directly as a vasoactive mediator in coronary arteries in HHcy. It is also unlikely that oxidation of protein cysteine residues by ONOO-22
impairs NO mediation in HHcy, because flow-induced responses of HHcy arteries were unaffected by dithiothreitol (Figure 2D)
. The hypothesis that protein nitrosation by ONOO- inactivates eNOS in HHcy could also be refuted because in vitro incubation of control vessels with authentic ONOO-, which results in substantial nitrosation of vascular proteins (Figure 3)
, did not affect flow-induced responses (Figure 2F)
. Furthermore, flow-induced dilations of HHcy coronary arteries were reversible by acute administration of superoxide scavengers (Figure 2, B and C)
. Nevertheless, our data do not rule out that chronic superoxide/ONOO--induced protein/lipoprotein modification (either tyrosine nitrosation or cysteine oxidation) affects other functions of coronary arteries and/or contribute to the development of arteriosclerosis.17,39,40
ONOO- may also elicit DNA single-strand breaks activating the poly(ADP-ribose) polymerase32
predisposing coronary vessels, especially when other risk factors are present, for pathophysiological alterations.25
Also, HHcy may trigger other cellular mechanisms (eg, activation of redox-sensitive genetic elements, production of cytokines,41
down-regulation of glutathione peroxidase33
) that can further aggravate vascular dysfunction and lead to arteriosclerotic alterations, isoprostane formation,6
lipid peroxidation,42
and smooth muscle proliferation.43
In conclusion, the present study demonstrated that flow-induced dilation of isolated small intramural coronary arteries is substantially impaired in hyperhomocysteinemic rats because of an enhanced production of superoxide, which decreases the bioavailability of NO to mediate the dilation through the formation of ONOO-. Such alterations in endothelial regulation of coronary circulation in HHcy could promote the development of arteriosclerosis and ischemic heart disease.
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Acknowledgements |
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Footnotes |
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Supported by grants from Hungarian National Scientific Research Funds (OTKA) (T-034779, T-33117), the National Heart, Lung, and Blood Institute (HL-46813, PO-1HL-43023), and the American Heart Association New York State Affiliate Inc. (00500849T, 0020144T, 0120166T).
Accepted for publication March 29, 2002.
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