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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:2032-2036.)
© 1995 American Heart Association, Inc.

Articles

The Interstitium of the Human Arterial Wall Contains Very Large Amounts of Extracellular Superoxide Dismutase

Pontus Strålin; Kurt Karlsson; Bengt O. Johansson; Stefan L. Marklund

From the Department of Clinical Chemistry (P.S., K.K., S.L.M.) and the Department of Anatomy (B.O.J.), Umeå University Hospital, Sweden.

Correspondence to Stefan L. Marklund, Department of Clinical Chemistry, Umeå University Hospital, S-901 85 Umeå, Sweden.

	Abstract

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Abstract The levels of the secreted, interstitially located extracellular superoxide dismutase (EC-SOD), the cytosolic copper-and-zinc–containing SOD (CuZn-SOD), and the mitochondrial manganese-containing SOD (Mn-SOD) were measured in the walls of human coronary arteries, proximal thoracic aortas, and saphenous veins. The blood vessel walls, particularly the arteries, were found to contain exceptionally large amounts of EC-SOD, whereas the levels of CuZn-SOD and Mn-SOD were relatively low compared with other tissues. Analysis of EC-SOD by immunohistochemistry indicates an even distribution in the vessel wall, including large amounts in the arterial intima. Arterial smooth muscle cells were found to secrete large amounts of EC-SOD and likely are the principal source of the enzyme in the vascular wall. The EC-SOD concentration in the human arterial wall extracellular space is high enough to efficiently suppress the putative pathological effects of the superoxide radical, such as oxidation of LDL and reaction with nitric oxide to form the deleterious peroxynitrite. The levels of EC-SOD in the aortic wall are found to vary widely among species and were on average 6440 U/g in humans, 4340 U/g in the cow, 2660 U/g in the pig, 160 U/g in the dog, 770 U/g in the cat, 2390 U/g in the rabbit, 90 U/g in the rat, and 3400 U/g in the mouse. There were only moderate differences in the amounts of CuZn-SOD and Mn-SOD. This wide variation in EC-SOD content suggests that the susceptibility to pathologies induced by superoxide radicals in the vascular wall interstitium should vary widely among species.

Key Words: superoxide • nitric oxide • oxygen free radicals • atherosclerosis • LDL

	Introduction

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The effects of the superoxide radical and derived products on blood vessel functions have attracted increasing recent attention. Direct damaging effects on the endothelium¹ and other vessel components, involvement in the oxidation of LDL^{2 3 4 5} and hence potential involvement in atherosclerosis, noxious interactions with NO·,^{6 7 8 9 10} and direct effects on vessel tonus¹¹ have all been reported. However, despite the potential importance of the superoxide radical, little is known about the endogenous protection of the extracellular space and cells of the vascular wall provided by SODs.

To assess the role of SODs in blood vessel homeostasis we undertook the present study, in which we determined in human coronary artery, aorta, and saphenous vein the contents of the three SOD isoenzymes: the secreted EC-SOD,¹² the cytosolic CuZn-SOD,¹³ and the mitochondrial matrix Mn-SOD.¹⁴ We find comparatively little CuZn-SOD and Mn-SOD but exceptionally large amounts of EC-SOD. For comparison, we also measured the SOD isoenzymes in the aortas of a number of other mammalian species and found considerable interspecies variation in EC-SOD content.

	Methods

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Extraction of the Vessel Wall
Macroscopically normal pieces (0.5 to 1.5 g) of human LAD, proximal thoracic aorta, and saphenous vein were cut out at autopsy within 48 hours after death. Thoracic aortas from the other mammals were collected within a few hours after death. The pieces were kept at -80°C before analysis. For extraction, frozen pieces were pulverized in a Braun Microdismembrator II (B Brown Biotech Inc), and the frozen powder was added to 10 vol of 50 mmol/L potassium phosphate, pH 7.4, with 0.3 mol/L KBr and a set of antiproteolytic agents (0.5 mmol/L PMSF, 3 mmol/L DTPA , 90 mg/L aprotinin, 10 mg/L pepstatin, 10 mg/L chymostatin, and 10 mg/L leupeptin). The homogenates were then sonicated and finally extracted for 30 minutes at 4°C. The extracts were centrifuged (20 000g for 15 minutes). Unless analyzed immediately, the supernatants were stored at -80°C.

SOD Activity Analysis
SOD enzymatic activity was determined by the direct spectrophotometric method, employing KO₂¹⁵ as modified.¹⁶ To distinguish between the cyanide-sensitive isoenzymes CuZn-SOD and EC-SOD and the resistant Mn-SOD, 3 mmol/L cyanide was used. One unit in the assay is defined as the activity that brings about a decay of O₂^-· concentration at a rate of 0.1 s^-1 in 3 mL of buffer. It corresponds to 8.3 ng human CuZn-SOD, 6.3 ng bovine CuZn-SOD, 8.6 ng human EC-SOD, and 65 ng bovine Mn-SOD. The "KO₂ assay" is carried out at pH 9.5 and at a relatively high superoxide concentration. In comparison, the xanthine oxidase–cytochrome C SOD assay¹³ is carried out under more physiological conditions, ie, neutral pH and low superoxide concentration. One unit in the KO₂ assay corresponds to about 0.024 units CuZn-SOD and EC-SOD and 0.24 units Mn-SOD in the xanthine oxidase assay. The KO₂ assay is thus 10 times more sensitive for CuZn-SOD and EC-SOD activity than for Mn-SOD activity. The results presented in the tables were not corrected for this effect.

Specific Analysis of EC-SOD
EC-SOD in human blood vessel wall extracts was determined by ELISA.¹⁷ There is no cross-reactivity with human CuZn-SOD. For conversion of results to activity units, 8.6 ng per unit was assumed.¹⁸

For the specific analysis of EC-SOD in vessel extracts from other species, chromatography on Con A–Sepharose (Pharmacia Biotech) was used. Unlike CuZn-SOD and Mn-SOD, the glycoprotein EC-SOD binds to the lectin concanavalin A. The procedure has been described previously,¹⁹ the only difference being that the extraction buffer described above was used as a solvent in all steps. The yield of EC-SOD in the procedure was tested with human blood vessel extracts. Seventy-five percent of the applied EC-SOD was found to be recovered as determined by ELISA, and all EC-SOD results for the other mammals were corrected accordingly. The CuZn-SOD activity of the extracts was then calculated as total cyanide-sensitive SOD activity minus (corrected) EC-SOD activity.

Protein and DNA Analysis
For protein analysis, Coomassie brilliant blue G-250 was employed,²⁰ standardized with human serum albumin. DNA concentration was determined with fluorimetry as a complex with bisbenzimidazole (Hoechst 33258)²¹ using calf thymus DNA as a standard.

Effect of Storage on SOD Activity
Since the human samples were collected from bodies stored under refrigeration up to 48 hours, the effects of storage on the various analyzed factors were determined. Small pieces (around 300 mg) of cow aorta, prepared under aseptic conditions, were stored in 1.5-mL capped tubes in a refrigerator at 5°C. Tubes were transferred to -80°C at 1.5 hours, 12 hours, 24 hours, and daily up to 6 days after death. Three 1.5-hour samples and two from the other storage times were then homogenized and analyzed as described above for the animal samples. There were no systematic increases or decreases in the activities of the SOD isoenzymes or the contents of protein or DNA in the daily samples over the 6-day period. The means of the parameters in the two pieces stored at 5°C for 6 days deviated at most 13% from the means of the pieces stored for only 1.5 hours.

Immunohistochemistry
Vessels for immunostaining (LAD, thoracic aorta, and saphenous vein) were obtained at autopsy within 48 hours of death or immediately during vessel surgery. Cryostat sections were fixed for 45 minutes in a 1% paraformaldehyde solution. An avidin–biotin–horseradish peroxidase system (Dakopatts) was used for immunostaining. Anti-EC-SOD antibodies, raised against recombinant human protein¹⁸ in goat and rabbit and purified by adsorption/desorption on EC-SOD immobilized on CNBr-activated Sepharose, were used at concentrations of 0.7 to 8.6 mg/L. As negative controls, primary antibodies were substituted with nonimmunized goat/rabbit IgG (2.4 to 11.6 mg/L).

Cell Culture
The arterial smooth muscle cell lines were initiated from pieces of human uterine artery as described by Fager et al.²² Their identity as smooth muscle cells was assessed by morphological appearance and by their expression of smooth muscle -actin²³ (Boehringer Mannheim GmbH), and analyzed by flow cytometry. The cells were maintained in Waymouth MB 752/1 medium containing 15% fetal calf serum, 10⁵ U/L benzylpenicillin, 100 mg/L streptomycin, 2 mmol/L glutamine, and 1 mmol/L sodium pyruvate and were studied between the fifth and eighth passages.

	Results

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Human Blood Vessel Walls
Human blood vessel walls, particularly the arteries, were found to contain exceptionally large amounts of EC-SOD, 10-fold more than average human tissues (Table 1). The levels of CuZn-SOD and Mn-SOD, on the other hand, were lower than in most other tissues. While in most tissues EC-SOD accounts for only a small percentage of the total SOD activity, the fraction in the arterial wall approaches 50%.

View this table: [in this window] [in a new window]   Table 1. Levels of SOD Isoenzymes in Human Blood Vessel Walls

Localization of EC-SOD by Immunohistochemistry
The distribution of EC-SOD in human aorta, LAD, and saphenous veins was studied by means of immunohistochemistry in samples from several individuals. The staining of all the samples was essentially identical. A result with a thoracic aorta specimen is presented as an example (see the Figure). EC-SOD is apparently evenly distributed throughout the wall, with significant amounts observed in all layers.

View larger version (20K): [in this window] [in a new window]   Figure 1. Immunostaining of EC-SOD in nondiseased thoracic aorta from a 40-year-old man, collected 48 hours postmortem. The anti–EC-SOD antibody used (1.4 mg/L) (A) was raised against the recombinant enzyme in rabbit. Nonimmunized rabbit IgG was used as a negative control (2.4 mg/L) (B). e indicates endothelium; i, intima; m, media; and a, adventitia. The upper pair of arrows mark the internal elastic lamina; the lower pair, the border between media and adventitia. Bar=200 µm.

SOD Isoenzymes in Aorta From Various Mammalian Species
We have previously found that the EC-SOD content of tissues shows a considerable interspecies variation, whereas the contents of CuZn-SOD and Mn-SOD vary to a lesser extent.²⁴ To investigate whether these differences also occur in blood vessels, we measured the levels of the SOD isoenzymes in the aortas from seven additional mammalian species (Table 2). We find a remarkable variation in the EC-SOD content, whereas the differences in CuZn-SOD activity are relatively small. The Mn-SOD activity displays an intermediate variation among the species.

View this table: [in this window] [in a new window]   Table 2. SOD Isoenzymes in Aorta From Various Mammals

Sources of EC-SOD in the Vascular Wall
Although the intracellular isoenzymes CuZn-SOD and Mn-SOD occur in all nucleated cell types, EC-SOD is expressed by only a few.²⁵ Expression by fibroblasts and glia cells has been demonstrated before, whereas other cell lines, eg, endothelial cells (n=6), lacked expression.²⁵ All investigated suspension-growing cell lines of hematological origin likewise lacked expression. To further explore potential sources of EC-SOD in the vascular wall, expression by arterial smooth muscle cells was examined (Table 3). The smooth muscle cell lines all secreted EC-SOD in large amounts, similar to those previously found for fibroblast cell lines. Since smooth muscle cells constitute the major portion of the cells occurring in the vascular wall, they should be the principal source of the EC-SOD existing in this location.

View this table: [in this window] [in a new window]   Table 3. Expression of EC-SOD by Cultured Human Smooth Muscle Cells

	Discussion

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The major finding of the present study is the exceptionally high EC-SOD content in the extracellular space of the human arterial wall. The CuZn-SOD and Mn-SOD contents are relatively low. The cell densities of the vascular walls are low, however, and a comparison with other tissues on the basis of U/mg DNA²⁶ indicates that the average content per cell of these intracellular isoenzymes is normal or slightly high. The present study, however, provides no information on the distribution of these intracellular isoenzymes among the various cell types in the vascular wall. Since the superoxide anion radical crosses membranes poorly,²⁷ the SOD isoenzymes exert their protective functions in their distinct compartments. For these reasons, we focus this discussion on EC-SOD and events in the vascular wall extracellular space.

The present (Table 3) and previous²⁵ analyses of EC-SOD expression by human cell lines indicate that the principal source of the enzyme in the vascular wall is the smooth muscle cells. EC-SOD shows high affinity for heparin and some related sulfated glycosaminoglycans^{28 29} and exists, in tissues, reversibly anchored primarily to heparan sulfate proteoglycans in the interstitial matrix and on cell surfaces.^{30 31} After secretion, the EC-SOD should slowly diffuse in the vascular wall and distribute itself according to amount and affinity of the glycosaminoglycans occurring in the various microenvironments. This process seems to result in a relatively even distribution of the enzyme to the various layers of the vessel wall (Figure). Assuming a distribution volume of 30% in the arterial wall, an average EC-SOD activity of 15 000 to 20 000 U/mL in the extracellular space can be estimated. CuZn-SOD, which is commercially available and has been widely used in similar studies, has an equivalent activity equal to 110 mg/L CuZn-SOD. The very high EC-SOD activity in the arterial interstitium, including the intima, could be important for the suppression of various pathological processes.

LDL oxidation has been suggested to be a primary step in atherogenesis.³² In several in vitro models of LDL oxidation, addition of CuZn-SOD has been shown to be protective,^{2 3 4 5 6} suggesting a potential involvement of the superoxide radical in the process in vivo. The high EC-SOD activity in the human arterial intima should effectively suppress any direct involvement of the superoxide radical in LDL oxidation.

NO· produced by the endothelium is a major physiological vasodilator.^{33 34} It also reduces the adhesion of platelets³⁵ and leukocytes³⁶ to the vascular wall and by terminating lipid peroxidation may protect LDL from oxidation.^{37 38} Nitric oxide synthase can also be induced in phagocytic cells and smooth muscle cells.³⁹ NO· reacts with superoxide at an essentially diffusion-limited rate to form the very toxic compound peroxynitrite.^{6 7} Peroxynitrite, which is in itself an oxidizing agent, may nitrate proteins⁸ and induce LDL oxidation¹⁰ and may decompose to other strongly oxidizing species.⁹ Thus, the interaction between superoxide and NO· reduces the physiological and protective effects of NO· and leads to the formation of toxic compounds. The extensive nitration of protein tyrosines found in human atherosclerotic lesions shows that significant amounts of peroxynitrite may be formed under pathological conditions in vivo.⁴⁰ With maximal stimulation of the endothelium of isolated rabbit aorta, NO· concentrations of 0.85 µmol/L have been measured in the wall,⁴¹ although in vivo the concentrations may be lower due to scavenging of NO· by hemoglobin.⁴² With the high rate constant for peroxynitrite formation, 6.7x10⁹ L·mol^-1·s^-1,⁷ it can be calculated that on the order of 19 000 U/mL (EC)SOD is needed to compete equally with 0.85 µmol/L NO· for superoxide radicals. Thus, the high EC-SOD activity in the human arterial wall interstitium should be sufficient to compete with basal concentrations of NO· but may allow significant formation of peroxynitrite under maximal agonist stimulation of the endothelium and when NO synthase is induced in other cell types. In several pathological situations the rate of superoxide formation is also increased in the arterial wall^{43 44 45 46 47} and may equal or exceed the rate of NO· formation, as indicated by the effects of administration of large amounts of SOD on NO·-induced responses. Thus, the injection of a heparan sulfate–binding SOD derivative reduced the blood pressure in spontaneously hypertensive rats,⁴³ addition of SOD enhanced acetylcholine-induced relaxation of aortas from diabetic rats,⁴⁴ and in vivo administration of liposome-encapsulated CuZn-SOD enhanced the response to acetylcholine of isolated aortic rings derived from cholesterol-fed rabbits.⁴⁵ All these studies were performed on species with less arterial wall EC-SOD than is found in humans, and the results emphasize the potential protective role of a high EC-SOD level of the arterial wall interstitium.

We have previously found considerable differences among mammalian species in organ EC-SOD contents.²⁴ Here we describe large differences in the levels in the aortic wall. One similarity among the species is that in all cases except rats and mice the arterial wall contains by far the largest amounts of EC-SOD of all organs analyzed, suggesting a particularly important role for the enzyme in this tissue. The rat species deviates from all other mammals in that the organ EC-SOD content is very low, but the plasma content is relatively high.²⁴ Unlike the EC-SOD of other species, rat EC-SOD is dimeric and has a low affinity for heparin and does not bind to heparan sulfate under physiological conditions.⁴⁸ In the mouse, the lungs and the aorta contain equally large amounts of EC-SOD. The wide interspecies differences indicate that the pathophysiological effects of superoxide radicals in the vascular wall should differ among species. In support of this suggestion we have shown that preincubation of rabbit aortic rings with recombinant human EC-SOD results in significant protection of NO·-mediated relaxation against superoxide formed by pyrogallol autoxidation.⁴⁹ The preincubation of the rabbit aortic rings resulted in a rise in (EC)SOD activity of about 5000 U/g wet weight, ie, to reach the levels of the human aorta. Thus, the difference in EC-SOD levels among species is an important factor to consider when extrapolating experimental findings in animal models to the situation in humans.

In summary, the very high EC-SOD activity of the human arterial wall interstitium and the large differences among mammalian species deserve attention in all studies on vascular wall pathology potentially involving oxidative stress.

	Selected Abbreviations and Acronyms

 

CuZn-SOD = copper-and-zinc–containing SOD EC-SOD = extracellular superoxide dismutase LAD = left anterior descending coronary artery Mn-SOD = manganese-containing SOD NO· = nitric oxide SOD = superoxide dismutase

	Acknowledgments

 
This study was supported by the Swedish Natural Science Research Council, grant 9204. The authors would like to thank Agneta Öberg, Eva Bern, and Els-Marie Öhman for their skillful technical assistance.

Received March 10, 1995; accepted August 25, 1995.

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