(Circulation. 2001;103:2408.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Oxidative Stress and Lipid Retention in Vascular Grafts
Comparison Between Venous and Arterial Conduits
From the Cardiovascular Research Center, Departments of Medicine (Cardiology) (Y.S., S.P., K.L.D., R.N., M.G.M., A.Z.) and Surgery (Cardiothoracic Surgery) (E.R., M.L.O., J.D.M.), Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Andrew Zalewski, MD, Thomas Jefferson University, Division of Cardiology, Suite 410N, 1025 Walnut St, Philadelphia, PA 19107. E-mail andrew.zalewski{at}tju.edu
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Abstract |
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Background—Because saphenous vein grafts (SVGs) exhibit greater cellular heterogeneity and worse clinical outcomes than arterial grafts (AGs), we examined oxidative stress and lipid retention in different vascular conduits.
Methods and Results—In a porcine model of graft interposition into carotid artery, superoxide anion (·O2-) was measured at 2 weeks after surgery. SVGs demonstrated increased ·O2- production compared with AGs (SOD-inhibitable nitro blue tetrazolium reduction, P<0.01). The NAD(P)H oxidase inhibitor diphenyleneiodonium (P<0.01) abolished SVG-derived ·O2-, whereas the inhibitors of other pro-oxidant enzymes were ineffective. The change in oxidative stress was also reflected by lower activity of the endogenous antioxidant superoxide dismutase in SVGs than in AGs (P<0.001). SVG remodeling was associated with increased synthesis of sulfated glycosaminoglycans and augmented expression of a core protein, versican. These changes were accompanied by SVGs retaining significantly more 125I-labeled LDL than AGs ex vivo (P<0.001). In hyperlipemic animals, lipid accumulation and oxidized epitopes were preferentially noted in the intima of SVGs at 1 month after surgery.
Conclusions—This study demonstrated significant differences in the biology of SVGs and AGs. SVGs exhibited higher oxidative stress, LDL accumulation, and the presence of oxidized epitopes. These findings suggest that proatherogenic changes in SVGs may commence early after surgical revascularization.
Key Words: atherosclerosis • bypass • grafting • remodeling
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is well recognized that saphenous vein grafts (SVGs) demonstrate lower patency rates than arterial grafts (AGs) in patients who undergo surgical coronary revascularization (reviewed by Motwani and Topol).1 Early attrition of SVGs has been attributed to thrombosis and rapid neointimal formation within the first year after surgery. After a period of clinical quiescence, the loss of SVG patency resumes because of graft atherosclerosis, manifested by occlusive lesions beginning at 3 to 5 years after revascularization. Neither better preoperative patient selection nor improved intraoperative handling of vascular conduits has been sufficient to eliminate the disparity between SVGs and AGs.2 3 Recent studies have increasingly focused on biological differences between venous and arterial conduits that may affect their response to surgery.4 5 In addition to structural differences (eg, less-developed elastic tissues), the cellular composition of veins is dissimilar to that of arteries. "Nonmuscle" fibroblasts, which are typically present in the adventitia of normal vessels, are common in the media of saphenous veins.6 7 These poorly differentiated cells are highly proliferative, and their population is further augmented by migration of adventitial and perivascular fibroblasts through the injured media.7 In contrast, smooth muscle cells (SMCs) of the arterial conduit exhibit less cellular activation, and adventitial fibroblasts are prevented from transmural migration by usually intact elastic tissues in AGs.
Oxidative stress is an important modulator of vascular cell
functions.8 Increased
generation of reactive oxygen species has been implicated in vascular
cell proliferation, apoptosis, and the induction of
transcriptional factors (eg, nuclear factor-
B), as well as oxidative
modifications of retained
lipoproteins.9 10 11 12
Under normal conditions, superoxide anion
(·O2-) is rapidly
inactivated by superoxide dismutase (SOD) stored in the
extracellular matrix of the tunica
media.13 14
Interestingly, fibroblast-rich adventitia generates more
·O2- than medial
SMCs, although the importance of this phenomenon has not been fully
explained.15 16
The differences in cellular composition between SVGs and AGs raise the
possibility that the activation of fibroblasts or the loss of SOD
activity results in the increase in oxidative stress in the media of
SVGs. In this study, we demonstrate that SVGs and AGs exhibit
dissimilar oxidative stress, lipoprotein accumulation, and oxidative
modification of retained LDLs. These findings illustrate that early
changes during SVG remodeling may contribute to their attrition because
of accelerated atherogenesis.
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Methods |
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Animal Model
A porcine model of a graft interposition in the common carotid artery was used as described.7 Briefly, saphenous veins were harvested without distension. Both carotid arteries were dissected free, an
2-cm section of the carotid artery
was excised, and reversed vein interposition grafting was performed.
The excised carotid artery was then grafted into the contralateral
carotid artery. The animals were given aspirin 650 mg/d PO. At the
times indicated, animals were euthanized and tissues harvested. A
separate group of animals (n=14) was placed on the atherogenic diet
modified from Weiner et al17
at 1 week before surgery and continued until graft harvest. These
animals demonstrated an increase in serum cholesterol from
79±8 mg/dL at baseline to >250 mg/dL within 3 to 5 days of the
atherogenic diet.
Measurement of
·O2-
Superoxide anion
(·O2-)
production was measured by SOD-inhibitable conversion of nitro
blue tetrazolium (NBT) to
formazan.15 16
Normal saphenous veins, arteries, SVGs, and AGs were harvested at 2
weeks after surgery. Vascular media was cut into strips and balanced in
phenol-free DMEM at 37°C in CO2 for 30
minutes. NBT (0.1 mg/mL in phenol-free DMEM) was added for 3 hours with
or without addition of SOD (1000 U/mL). The reaction was terminated by
addition of 0.5N HCl. To extract formazan, tissues were pulverized in
liquid nitrogen and dissolved in 100% pyridine at 80°C for 30
minutes. Supernatants were read at 540 nm, and NBT reduction was
calculated as follows: NBT reduction=AxV/(TxExL), where A is
absorbance; V, volume of solubilizing solution; T, time of incubation
with NBT (minutes); E, extinction coefficient=0.72 mmol/mm;
and L, length of light travel through the solution (10 mm). The
SOD-inhibitable NBT reduction was calculated as a measure of
·O2- (pmol · mg
wet wt-1 ·
min-1). In some experiments, tissues were
incubated with enzyme inhibitors to determine the source of
·O2-. The
following inhibitors were used: diphenyleneiodonium [DPI,
an inhibitor of NAD(P)H oxidase, 100 µmol/L], oxypurinol
(an inhibitor of xanthine oxidase, 300 µmol/L), rotenone
(an inhibitor of mitochondrial respiration, 50 µmol/L),
and
N
-nitro-L-arginine
methyl ester (L-NAME; an inhibitor of NO synthase, 1
mmol/L).
SOD Activity
SOD activity was measured by SOD-dependent inhibition
of cytochrome c reduction
catalyzed by xanthine/xanthine
oxidase.18 19
Vascular media was homogenized in 10 vol 50 mmol/L
potassium phosphate (pH 7.4) containing 0.3 mol/L KBr and a cocktail of
protease inhibitors (0.5 mmol/L PMSF, 90 mg/L
aprotinin, 10 mg/L pepstatin, 10 mg/L leupeptin) followed by sonication
(10 seconds) and extraction at 4°C for 30 minutes. The extracts were
centrifuged at 20 000g
for 30 minutes. The supernatants were added to the reaction mixture,
consisting of 0.1 mmol/L EDTA, 0.090 mmol/L xanthine, and
0.018 mmol/L cytochrome c
(pH 7.4). SOD activity was assessed by monitoring the inhibition of
xanthine oxidase–mediated cytochrome
c reduction, with the
absorbance measured at 550 nm over 3 minutes, as
described.19
GAG Synthesis
Dry defatted tissue (DDT) was digested with papain (7
U/mL) in 100 mmol/L sodium acetate, 5 mmol/L cysteine, 5
mmol/L EDTA at 60°C for 24 hours. After precipitation with 0.1%
cetylpyridium chloride in 0.1 mol/L sodium citrate (pH 4.8) for 2 hours
at 37°C, the pellets were washed with ethanol, air-dried, and
dissolved in distilled water (100 mg/mL). Sulfated GAG was measured by
dye-binding assay (Blyscan, Biocolor Ltd). Briefly, dye reagent
(1,9-dimethylmethylene blue), which was added to the samples, binds to
sulfated GAG and forms the insoluble
complex.20 GAG-bound dye was
recovered with a dissociation reagent, and the absorbance of the
recovered dye was measured in a spectrophotometer at 656 nm. Sulfated
GAG (µg) in vascular tissues was calculated from the calibration
curve by use of the GAG standard. The values were normalized per mg of
DDT.
LDL Retention Ex Vivo
To assess LDL retention in vascular tissues, normal
saphenous veins, normal arteries, SVGs, and AGs were harvested at 14
days after surgery. After the removal of the adventitia and
endothelium, vessels were cut into 5-mm fragments
and placed in 24-well plates. They were then incubated with
125I-labeled LDL (1 mg/mL, 30 cpm/ng) in
DMEM (0.5 mL/well) for 24 hours with gentle rocking at 37°C. Tissues
were rinsed 5 times (15 min/wash) and blotted dry. Samples were counted
in a gamma counter, and values derived from empty wells with
125I-labeled LDL were subtracted. LDL
retention was expressed per wet weight (mg), DDT (mg), surface area
(mm2), and protein content
(ng).
Immunohistochemistry
The Vectastain Elite ABC system (Vector
Laboratories) was used as previously
described.21 Tissues were
fixed in HistoChoice (Amresco) and processed for paraffin-embedded or
frozen sections. They were incubated with primary antibodies for 1
hour, followed by biotinylated secondary horse anti-mouse antibodies
(1:2000, Vector Laboratories) for 1 hour. They were visualized with DAB
substrate, followed by counterstaining with hematoxylin. Monoclonal
antibodies against the hyaluronate-binding region of human versican
(1:200, Developmental Studies Hybridoma Bank), apolipoprotein B (apoB)
(1:50, Biodesign), and oxidized epitopes (1:50, Biodesign) were used.
Negative controls included nonimmune serum instead of primary
antibody.
Statistical Analyses
Data were expressed as mean±SEM. The statistical
significance regarding multigroup comparisons was determined by ANOVA.
A value of P<0.05 was
considered significant.
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Results |
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Oxidative Stress in Vascular Grafts
Reactive oxygen species modulate several cellular functions important in vascular remodeling. Accordingly, we have examined oxidative stress in venous and arterial grafts measuring intragraft pro-oxidant and antioxidant properties. As shown in Figure 1
, basal production of
·O2-
(SOD-inhibitable NBT reduction) was higher in saphenous veins (n=6,
P<0.01) than in normal
arteries (n=6) before grafting. Importantly, vein
arterialization further upregulated levels of
·O2- in SVGs
(n=5, P<0.01) compared with
AGs (n=7) at 2 weeks after surgery. To determine the source of
·O2- in SVGs,
several inhibitors of known oxidant enzymes were used. The
incubation of SVGs with DPI [100 µmol/L, NAD(P)H oxidase
inhibitor] almost entirely abolished
·O2- (reduction
by >95%), whereas the inhibitors of mitochondrial
dehydrogenase, xanthine oxidase, or nitric oxide synthase showed no
effects
(Figure 2).
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P<0.01 vs AGs; n=5 to 7 per bar.
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Because the graft oxidative stress depends not only on the
generation of
·O2- but also on
antioxidant properties of the tissue, we examined whether the
arterialization of saphenous veins affects SOD activity. As
illustrated in
Figure 3, normal veins (n=5) and arteries (n=5) demonstrated
comparable SOD activity (cytochrome
c reduction assay).
Nonetheless, SVGs (n=8,
P<0.001) exhibited a
significant loss of SOD activity, whereas AGs (n=7) showed no changes
at 2 weeks after surgery.
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Expression of Sulfated GAG and Core Protein
Proteoglycans
Vascular graft adaptation includes the changes in the
extracellular matrix, which may influence the properties of the
conduits. To this end, we examined the accumulation of sulfated GAG
(dye-binding assay) in grafts harvested at 2 weeks after surgery. Not
surprisingly, normal saphenous veins (n=8, 2.4±0.8 µg/mg DDT) and
arteries (n=4, 6.3±0.8 µg/mg DDT) differed in the amount of sulfated
GAGs before surgery. Importantly, however, vein
arterialization (n=8) was accompanied by a significant
accumulation of sulfated GAG (3.6±0.8-fold increase,
P<0.01 versus normal vein). In
contrast, AGs (n=4) showed no increase in the amount of GAG
(0.68±0.4-fold increase, P=NS
versus normal artery). Because sulfated GAGs constitute side chains of
proteoglycans, we further verified the above results examining the
expression and localization of a representative core
protein (versican). As shown in
Figure 4, versican immunoreactivity was elevated in the
neointima at 2 weeks. In contrast, AGs showed no apparent
changes in versican expression (not shown).
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Lipid Retention and Its Modification After
Grafting
The differences in vessel permeability and composition
(eg, sulfated GAG content) may increase lipid retention. To address
this issue, normal saphenous veins, arteries, SVGs, and AGs were
harvested, and 125I-LDL retention was
examined ex vivo. As illustrated in the
Table,
intact saphenous veins retained more LDL than arteries, which most
likely reflected their dissimilar permeabilities, although the
difference did not reach statistical significance. At 2 weeks after
surgery, SVGs trapped even more radiolabeled LDL over the 24-hour
period than normal saphenous vein, normal artery, or AG
(P<0.001) regardless of
several methods used for data normalization. In contrast, no changes in
LDL accumulation were seen in AGs. Because the differences in LDL
retention in SVGs and AGs ex vivo do not include
hemodynamic factors present in vivo, we verified
the intragraft accumulation of lipid in hyperlipemic animals (serum
cholesterol 545±49 mg/dL, n=14). As shown in
Figure 5, AGs showed no apparent lipid accumulation, whereas
SVGs contained both extracellular and intracellular deposits of lipid
(oil red O stain). Focal accumulation of apo B and oxidized epitopes
was localized in the regions of the neointima containing
versican
(Figure 5).
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Discussion |
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Major findings of this study point to several biological characteristics that distinguish SVGs from AGs. The arterialization of saphenous veins is marked by a significant shift in the oxidative stress, an accumulation of sulfated proteoglycans, and early lipid retention.
The balance between reactive oxygen species and endogenous antioxidants is an important homeostatic mechanism in vascular tissues.8 Studies of the arterial system have underscored a preferential generation of ·O2- by adventitial fibroblasts compared with medial SMCs.15 16 Although cellular heterogeneity of the venous media, which contains fibroblasts, could contribute to the higher levels of ·O2-, additional studies are necessary to confirm cell-dependent generation of oxidative stress in SVGs.7 The upregulation in ·O2- in arterialized veins could also be attributed to several additional factors. They include pulsatile stretch and medial injury sustained by SVGs.22 23 24 25 In fact, focal vascular trauma has been shown to upregulate ·O2- in the arterial system,26 27 although studies of vascular grafts have been limited.28 Numerous growth factors released at the site of tissue injury, including thrombin, are known to increase NAD(P)H oxidase activity.29 As shown in the present study, an inhibitor of NAD(P)H oxidase almost entirely abolished ·O2- production in SVGs. These findings are consistent with an emerging role of NAD(P)H oxidase as a primary source of ·O2- in the vasculature.30
Two mechanisms aimed at removing
·O2- also appear
to be impaired in venous grafts. First, venous
endothelial cells are less effective than
arterial cells in the synthesis of nitric oxide, which
interacts with
·O2-.4
Second, as shown in the present study, the overall activity of SOD,
a major antioxidant enzyme, is attenuated in SVGs. It remains to be
determined which form of SOD is reduced, although its extracellular
form is less abundant in the
veins.14 The observed
oxidative stress could explain the higher cell proliferation seen early
after vein arterialization but generally absent in
AGs.7 Furthermore,
redox-sensitive transcriptional factors (eg, nuclear factor-B) may
induce the expression of adhesive molecules, such as vascular cell
adhesion molecule-1, which in turn promote the influx of blood-borne
inflammatory cells into the healing
SVGs.31 These mechanisms
often lead to excessive neointimal formation and early
occlusive lesions in SVGs.
Although vein graft atherosclerosis is clinically manifested several years after surgery, the results of the present study suggest that this process begins much earlier. Normal saphenous veins retained more LDL ex vivo owing to less developed elastic laminae and probably higher permeability. Importantly, LDL retention significantly increased after vein arterialization (2 weeks), in contrast to AGs. In hypercholesterolemic animals, lipid accumulated in the neointima of SVGs. In addition to vessel permeability and hemodynamic factors, lipid retention is influenced by extracellular matrix components.32 In particular, sulfated GAG proteoglycans derived from proliferating cells have higher binding affinity to LDL.33 Our previous studies have shown that vascular tissues rich in proliferating fibroblasts produced higher amounts of sulfated GAG and exhibited avid lipid retention compared with differentiated SMCs.34 Thus, oxidative stress and the synthesis of matrix proteins, which retain LDL, may promote oxidative lipid modifications and create conditions promoting early onset of SVG atherogenesis. This study has important clinical implications, providing biological rationale for the use of arterial conduits for coronary revascularization. In those patients in whom SVGs cannot be avoided, it remains to be determined whether the inhibition of vascular NAD(P)H oxidase (eg, with ACE inhibitors) reduces SVG attrition and cardiovascular events. Furthermore, early lipid retention in SVGs confirms the need for aggressive correction of lipid abnormalities in postbypass patients.35
In summary, this study demonstrated significant differences in the biology of SVGs and AGs. Early changes in SVGs are characterized by oxidative stress due to higher production of ·O2- and lower activity of SOD. Furthermore, SVGs increase the synthesis of sulfated GAG proteoglycans, which is associated with LDL retention. These findings also suggest that although SVG atherosclerosis is clinically manifested 3 to 5 years after surgery, proatherogenic changes may commence early after surgical revascularization.
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Acknowledgments |
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This study was supported by the National Institutes of Health (HL-44150 and HL-60672) and the John S. Sharpe Foundation. We acknowledge the technical assistance of Dian Wang.
Received April 28, 2000; revision received December 28, 2000; accepted January 10, 2001.
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