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1 Program in Biomedical Engineering, Departments of Medicine and Physiology, State University of New York, Stony Brook 11794; and 2 Program in Biochemistry and Structural Biology, Department of Pharmacology and Weill Medical College of Cornell University, New York 10021
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.
diabetes; endothelial dysfunction; vasculopathy; nitric oxide synthase; electrospray ionization-mass spectrometry
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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DEVELOPMENT OF MICROVASCULAR and macrovascular complications in diabetic patients has been linked to the quality of glycemic control (8, 22, 31). The finding that blood pressure is elevated in normal subjects during hyperglycemic clamp (14) indicates that elevated glucose can directly trigger vasoconstriction in diabetic patients. Although a dysfunction in nitric oxide (NO) biosynthesis or bioactivity is strongly implicated in the pathogenesis of diabetic vasculopathy (4, 18, 25, 26), the mechanistic basis for NO dysfunction is uncertain.
One possibility is that the chronic vasoconstrictive effect of hyperglycemia results from accumulation of advanced glycation end products (AGE) in the subendothelial compartment, leading to NO quenching and a loss of NO-induced smooth muscle vasorelaxation (3); this scenario is, perhaps, not the only one. An additional mode of glucose action is suggested by the observation that endothelium-dependent vasodilatation is already impaired within 15 min after the initiation of hyperglycemia (2), a period that is far too brief to allow significant buildup of AGE.
Using an in vitro microassay for direct real-time electrochemical monitoring of NO production by endothelial cells and purified recombinant endothelial nitric oxide synthase (eNOS), in conjunction with electrospray ionization (ESI)-mass spectrometry (MS) to identify chemical interactions that occur between glucose and NO, we demonstrate a direct NO-scavenging capacity of D-glucose. Thus rapid chemical inactivation of NO by glucose may be an important contributor to the dampened NO bioactivity observed in blood vessels from diabetic patients.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell culture. Microvascular endothelial cells were previously established and characterized by our laboratory; these SV-40-immortalized cells established from explant cultures of microdissected rat renal resistance arteries express receptors for acetylated low-density lipoprotein, immunodetectable von Willebrand antigen, and are capable of capillary tube formation (30). Cells were grown on gelatin-coated dishes in medium 199 culture medium (Mediatech, Washington, DC) supplemented with 5% FBS (HyClone Laboratories, Logan, Utah), 100 U/ml penicillin, and 100 µg/ml streptomycin (GIBCO-BRL, Gaithersburg, MD).
Measurement of eNOS activity with NO-selective microelectrodes in vitro. Recombinant bovine eNOS protein was purified from Escherichia coli that had been transformed with independent vectors for expression of eNOS and Gro ELS, as previously described (15). NO concentration ([NO]) was monitored with porphyrin-electroplated, nafion-coated, carbon-fiber electrodes (30 µm OD) manufactured according to Bio-Logic Instruments instructions (Grenoble, France; see Ref. 28). The electrode oxidation current was low-pass-filtered at 0.5 Hz and sampled every 2 s. Measurements were made using constant potential amperometry (0.7 volts) and a highly sensitive potentiostat (InterMedical, Nagoya, Japan). Calibration of the electrode was performed before each experiment using dilutions of freshly prepared NO-saturated Krebs-Ringer solution.
The NO-selective and reference electrodes were equilibrated in a buffer at room temperature with constant stirring until a stable baseline current was obtained. The composition of the buffer was 50 mM Tris · HCl, pH 7.4, 500 µM NADPH, 5 µM FAD, 5 µM FMN, 100 nM calmodulin, 10 µM CaCl2, and 20 µM L-arginine. To avoid interference by high levels of tetrahydrobiopterin (BH4), which is electroactive and unstable at physiological pH, 1 µM BH4 was added to the eNOS aliquots 12-24 h before the measurements. This permitted binding of the cofactor to eNOS, which stabilizes bound BH4 while allowing unbound BH4 to decay away. After obtaining a stable baseline, 25 pmol eNOS was pipetted to the cuvette, and the electrochemical response was recorded continuously. For the determination of the effect of glucose, desired glucose concentrations were added to the cuvette before the administration of eNOS. When necessary, 0.2-2 mM N
-methyl-L-arginine
(L-NMMA) was added to the solution to verify the NO
dependence of the recorded electrode current. At the completion of
experiments, electrode calibration was confirmed by evaluating responses to reference solutions of NO-saturated deionized water.
ESI-MS of D-(+)-glucose and products formed upon reaction with acidified NaNO2. Spectra were acquired on a Quattro II extended mass range (1-8,000 Da) triple quadrupole mass spectrometer (Micromass UK Limited, Manchester, UK) interfaced to a Windows NT workstation utilizing MassLynx version 2.3 software (Micromass UK Limited). The mass spectrometer was scanned in the negative ionization mode, with a source temperature of 70°C and a 3.2-kV capillary potential. For tandem mass spectrometry (MS/MS), a collision-induced dissociation energy of 10 volts was applied. Samples contained 10 mM D-(+)-glucose and 10 mM formic acid in the absence or presence of 10 mM NaNO2. After incubation at 37°C for 30 min, a 100 µl aliquot of each reaction mixture was diluted with 900 µl of methanol-water-formic acid (94:4:2) and continuously infused into the mass spectrometer's coaxial probe at a rate of 0.3 ml/h.
Statistics. Statistical analyses were performed using a paired or unpaired Student's t-test, with P < 0.05 considered statistically significant. All values are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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NO production by cultured endothelial cells.
Rat renal microvascular endothelial cells (RMVEC) were incubated in
Krebs-Henseleit-HEPES buffer supplemented with 100 µM L-arginine and 5 mM D-glucose. Cells were
repeatedly stimulated with 1 µM bradykinin at 30-min intervals to
elicit NO production; once a maximal NO response was obtained, the
agonist was removed by changing the bath. These treatments resulted in
a series of NO responses of consistent amplitude (not significantly
diminished compared with the initial response; see Fig. 1). The same
time course of bradykinin stimulation was repeated under identical conditions, except that the buffer glucose concentration was increased sixfold to 30 mM. As shown in Fig. 1, the
amplitude of consecutive responses to bradykinin was reduced by ~30%
in high-glucose buffer. These data indicate that free [NO] is
diminished in a high-glucose environment. Furthermore, NO production by
RMVEC stimulated by the calcium ionophore A-23187 was compared in the
following two groups of cells: those bathed in control Krebs' buffer
(5 mM glucose) and those bathed in buffer with 30 mM glucose. In accord
with observations using bradykinin as stimulus, NO responses to A-23187 were significantly less in the high-glucose buffer. Figure
2 summarizes dose-response relations
between the concentration of D-glucose and the
A-23187-induced NO release. Although some decline in NO release was
observed at 20 mM glucose, a statistically significant decrease was
documented at 30 mM. Furthermore, 30 mM L-glucose exhibited
the same effect on A-23187-induced NO release in contrast to the
unperturbed NO production in the medium made equiosmolar with the
addition of NaCl. The dampened NO detection observed with high glucose
could potentially arise from inhibition of endothelial NO synthesis or
abbreviation of the NO life time.
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In vitro NO generation by recombinant eNOS.
In vitro studies were performed where the activity of purified
recombinant bovine eNOS was continuously monitored using an NO-selective porphyrinic microelectrode. As shown in Fig.
3, addition of eNOS to the reaction
buffer resulted in immediate detection of an NO signal that was
attenuated upon addition of the prototypic NOS inhibitor
L-NMMA. Detection of NO was optimal with the electrode holding potential of 0.7 mV that was employed for these measurements; when the electrode holding potential was reduced to 0.4 mV, electrode current was not detectably affected by either eNOS-derived NO or
solutions of purified NO gas (data not shown). These findings demonstrate selectivity of NO detection by the amperometric technique and validate the method as an effective means to directly measure levels of eNOS-derived NO. Addition of D-glucose to
NO-forming enzyme reactions resulted in a rapid and dose-dependent
decrease in steady-state electrode current, consistent with a
diminished NO life time or synthesis rate (Fig. 3). Notably, glucose on
its own did not affect the electrode current (Fig.
4). To distinguish whether the apparent
glucose-induced lowering of [NO] resulted from accelerated NO loss,
in a next series of experiments we studied the effect of glucose on
[NO] in solutions of pure NO gas.
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ESI-MS/MS of D-(+)-glucose, before
and after treatment with acidified NaNO2.
Only charged species can be identified by MS; accordingly, a neutral
carbohydrate such as D-(+)-glucose is poorly detected. Nonetheless, negative ion monitoring ESI-MS revealed a prominent peak
for D-glucose at 179 Da, reflecting the deprotonated
species (native glucose = 180.2 Da). Because NO has a mass of 30 Da, the addition of NO to deprotonated glucose would predictably yield a species with mass 209 Da. Negative ion scanning ESI-MS of acidified glucose solution failed to identify any ions in the mass range of 206 to 213 Da (Fig. 5A). In
contrast, addition of nitrite to acidified glucose resulted in the
rapid appearance of two novel negative ion species at 208.5 and 210.4 Da (Fig. 5B). These ions are attributed to the product of NO
addition to deprotonated D-glucose, followed by loss or
gain of a hydrogen atom.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The rapidity of blood pressure elevation after establishment of hyperglycemia in normal volunteers (14) indicates that high glucose levels trigger functional alterations in vasomotor control. Three NO-based mechanisms have been invoked to explain this phenomenon: 1) inhibition of eNOS activity, 2) abbreviation of NO bioavailabilty, and 3) diminished capacity of NO to activate guanylyl cyclase (9, 6, 21). Studies presented herein demonstrate a direct NO-scavenging effect of glucose, providing a molecular explanation for abbreviated NO bioavailabilty. Specifically, the data obtained with cultured cells showed that elevated NO levels, in response to both receptor-dependent (bradykinin) and receptor-independent (calcium ionophore) activators of eNOS, were consistently diminished in high-glucose Krebs buffer compared with control buffer. Together with in vitro findings that elevated glucose diminished steady-state levels of NO derived from purified recombinant eNOS, it appeared that glucose could suppress eNOS activity. However, a similar diminution in NO levels was observed in the absence of eNOS, when glucose was added to solutions of purified NO gas. This latter finding strongly suggested that glucose abbreviates the NO life time, and this phenomenon can explain the observed lowering of [NO] after an acute elevation in glucose concentration. To examine whether NO can chemically react with glucose, mass spectrometric analyses were performed.
ESI-MS/MS analysis directly revealed that glucose undergoes addition of 30 Da upon exposure to a nitrosating environment (acidified nitrite). Because 30 Da is the mass of NO, this finding suggests that a single molecule of NO adds to glucose, presumably to a hydroxy-oxygen atom. Specification of the precise site of NO addition to glucose, based on molecular fragmentation analysis of this adduct, was complicated by the equal masses of NO and HCOH fragmentation units of glucose. Accordingly, we are unable to assign a precise structure to the NO-glucose product. We are nonetheless able to confirm by MS that glucose can capture NO (at low yield with regard to glucose) to form a yet unspecified addition product. The disappearance of NO in the form of this reaction product may be sufficient to explain the observed ability of high glucose (30 vs. 5 mM) to lower [NO] in biological solutions.
Glucose scavenging of NO can explain a host of earlier observations in which hyperglycemia has been linked to a diminished availability of NO in blood vessels. It has long been appreciated that isolated vascular rings, incubated in media with elevated glucose concentration, show impaired relaxation in response to NO-dependent vasodilators such as ACh (26). Exposure of endothelial cells to elevated glucose concentration has also been associated with reduced bradykinin-stimulated cGMP formation in RFL-6 reporter cells (17). Similarly, it has been demonstrated that acute hyperglycemia enhances NO degradation by endothelial cells, resulting in decreased endothelium-derived relaxing factor bioactivity (10). In normal human subjects, elevation of plasma glucose to 270 mg/dl caused a marked reduction in NO-mediated vasoactivity, leading to increased systolic and diastolic blood pressure and decreased leg blood flow within 30 min after initiation of the hyperglycemic clamp (9). It should be emphasized that these acute effects of glucose occur on the background of the insulin or insulin-like growth factor I-induced chronic vasodilation characteristic of uncomplicated diabetes mellitus (Ref. 28 and references therein). Furthermore, the observed acute effects of high glucose levels are independent of its chronic effects mediated via kinases or inducible NO synthase (1, 11, 29).
In addition to promoting endothelial cell dysfunction, the observed reaction of NO with glucose may have far-reaching sequelae for other NO targets. For instance, elevated ambient glucose levels reduced NO-dependent cGMP production with an apparent IC50 of 30 mM in human neuroblastoma cells, suggesting that the proposed mechanism of NO inactivation by glucose plays a role in the development of diabetic neuropathy (21). J774 macrophages incubated in media with elevated glucose concentration showed significantly reduced NO production in response to stimulation with lipopolysaccharide (29). Furthermore, the NO dependence of early phases of glucose-stimulated insulin secretion should alert to the possibility that decreased availability of NO may result in defective insulin secretion (20, 22). In addition, reduced bioavailability of NO can compromise insulin-stimulated glucose uptake in skeletal muscles, a process that requires NO (19). Hence, the reaction of NO with glucose, described herein, may be implicated in a host of pathophysiological processes resulting in the impaired macrophage and neuronal cell functions, insulin secretion, and glucose utilization, thus not only exacerbating glucose control but also promoting neurological and immunological complications. The aggregate effect of NO scavenging by glucose on vascular dysfunction and carbohydrate metabolism needs further investigation.
In summary, endothelial cells incubated in high-glucose buffer exhibit blunted NO responses to two eNOS agonists, bradykinin and A-23187. In vitro monitoring of NO production by eNOS suggested that glucose addition decreases either NO production or life time. Experiments with glucose additions to aqueous solutions of pure NO supported the latter possibility, namely, a glucose-mediated decline in NO life time. Finally, electrospray MS/MS analysis directly demonstrated that glucose can form a chemical adduct with NO. Based on these data, we conclude that glucose is capable of scavenging NO and predict important in vivo consequences for such reactions. Specifically, we hypothesize that acute hyperglycemia may elevate arterial blood pressure by diverting NO to glucose and away from smooth muscle cell targets of vasorelaxation. Loss of NO to glucose may similarly attenuate other important actions of endothelium-derived NO in the blood vessel wall; these include inhibition of smooth muscle proliferation, preventing platelet adhesion and aggregation, and limiting diapedesis of polymorphonuclear cells and monocytes (5, 7, 12, 13, 16, 24, 27). The extent to which glucose/NO adducts accumulate in plasma of diabetic patients, the precise chemical identities of these products, sites of formation (intra- or extracellular), metabolic fates, and potential to serve as precursor molecules for subsequent release of NO or other bioactive species all remain to be explored.
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ACKNOWLEDGEMENTS |
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These studies were supported in part by National Institutes of Health Grants DK-45462, DK-54602 (M. S. Goligorsky), HL-50656, HL-44603, and RR-11360 (S. S. Gross).
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. S. Goligorsky, Dept. of Medicine, State Univ. of New York, Stony Brook, NY 11794-8152 (E-mail: mgoligorsky{at}mail.som.sunysb.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 July 2000; accepted in final form 7 November 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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 M. C. Lansang and N. K. Hollenberg Renal Perfusion and the Renal Hemodynamic Response to Blocking the Renin System in Diabetes: Are the Forces Leading to Vasodilation and Vasoconstriction Linked? Diabetes, July 1, 2002; 51(7): 2025 - 2028. [Abstract] [Full Text] [PDF]
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