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(Circulation. 1995;91:1129-1134.)
© 1995 American Heart Association, Inc.

Articles

Evidence That Angiotensin II Is Present in Human Monocytes

Takanari Kitazono, MD; Richard C. Padgett, MD; Mark L. Armstrong, MD; Pamela K. Tompkins; Donald D. Heistad, MD

From the Departments of Internal Medicine and Pharmacology, Center on Aging and Cardiovascular Center, University of Iowa College of Medicine, and Veterans Administration of Medical Center, Iowa City, Iowa.

Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.

	Abstract

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Background The purpose of the present study was to determine whether human monocytes and polymorphonuclear leukocytes contain angiotensins I and II.

Methods and Results Human mononuclear and polymorphonuclear leukocytes were isolated from blood. To identify angiotensins in human leukocytes, we performed immunocytochemistry using both alkaline phosphatase and fluorescence methods. With light microscopy immunocytochemistry with akaline phosphatase, prominent staining of angiotensin II was observed in mononuclear leukocytes. Angiotensin I was also demonstrated in mononuclear leukocytes, but the signal was less pronounced than for angiotensin II. Polymorphonuclear leukocytes showed very little staining for angiotensin II. Fluorescence immunocytochemistry also demonstrated angiotensin II in mononuclear leukocytes. Angiotensins I and II in homogenate of leukocytes were quantified by radioimmunoassay. The concentration of angiotensins I and II in mononuclear leukocytes was 355±216 (mean±SEM) and 2331±106 fmol/mg protein, respectively, and the concentration in polymorphonuclear leukocytes was 36±10 and 336±120 fmol/mg protein.

Conclusions These findings suggest that human mononuclear leukocytes contain large amounts of angiotensin II and lesser amounts of angiotensin I. Human polymorphonuclear leukocytes contain small amounts of angiotensin I and II.

Key Words: leukocytes • renin • angiotensin • radioimmunoassay

	Introduction

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A local renin-angiotensin system may exist in several tissues, including vascular endothelium, brain, and heart.^{1 2 3 4 5 6} Recently, Gomez et al⁷ reported that rat mononuclear leukocytes synthesize and release angiotensinogen. Leukocytes also contain cathepsin G, which can convert angiotensinogen and angiotensin I to angiotensin II^{8 9 10} and angiotensin-converting enzyme.¹¹ Thus, it is possible that leukocytes are a mobile renin-angiotensin system.

Activation of the renin-angiotensin system may contribute to the development of vascular lesions in hypertension and atherosclerosis.^{12 13 14} Monocytes have been observed to infiltrate the wall of blood vessels, and it has been proposed that they contribute to vascular lesions.^{15 16} Angiotensins have been identified in murine macrophages,^{17 18} and a preliminary report suggests that angiotensin II may be present in human polymorphonuclear leukocytes.¹⁹ The presence of angiotensins in monocytes and/or macrophages might have important implications for the development of vascular lesions.

The goals of the present study were to determine whether human leukocytes contain angiotensin, whether the peptide is present predominantly in polymorphonuclear leukocytes or monocytes, and whether angiotensin I or II is the predominant peptide in human leukocytes. To reach these goals, two different approaches were used. First, angiotensins I and II were identified in human mononuclear and polymorphonuclear leukocytes using two types of immunocytochemistry. Second, angiotensins I and II were measured by radioimmunoassay in homogenate from human mononuclear and polymorphonuclear leukocytes.

	Methods

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Preparation of Leukocytes
Human mononuclear and polymorphonuclear leukocytes were isolated from blood by a histopaque centrifugation method as described previously.²⁰ Briefly, 300 mL venous blood was obtained from 20 healthy volunteers (age, 20 to 35 years). After erythrocytes were precipitated by incubation with 3% dextran, both mononuclear and polymorphonuclear leukocytes were isolated by histopaque centrifugation.²¹ The preparation of mononuclear leukocytes consisted of approximately 30% monocytes, 65% lymphocytes, and 5% neutrophils. In the preparation of polymorphonuclear leukocytes, more than 95% of the leukocytes were neutrophils. Cell viability was assessed by trypan blue (0.1%) exclusion.

Light Microscopy Immunocytochemistry
Light microscopy immunocytochemistry was performed by an alkaline phosphatase method. Cell smears were prepared on glass slides and dried at room temperature. The slides were fixed in 3% formaldehyde and 1% glutaraldehyde solution for 30 minutes. After cells were permeabilized with 0.8% Triton X-100 solution and blocked, the smears were incubated overnight with a rabbit antiserum to angiotensin I or II diluted 1:200 at 4°C. A control study was performed with healthy rabbit serum substituted for primary antibody and with primary antibody preadsorbed with standard human angiotensin I or II. The smears were incubated with biotin-conjugated anti-rabbit Ig G and avidin-conjugated alkaline phosphatase. After they were washed, the smears were incubated with naphthol-AS-BI-phosphate/fuchsin. The slides were counterstained with hematoxylin and eosin solution.

Fluorescence Immunocytochemistry
Cell suspensions of both mononuclear and polymorphonuclear leukocytes were fixed in 3% buffered formalin solution for 60 minutes. After cells were permeabilized with 0.8% Triton X-100 solution and blocked, the fixed cells were incubated overnight with a rabbit antiserum to angiotensin II diluted 1:200 at 4°C. A control study was performed with healthy rabbit serum substituted for primary antibody and with primary antibody preadsorbed with standard human angiotensin I or II. The cells were incubated with FITC-conjugated goat antibody against rabbit Ig G. The cells were mounted with aqueous mounting media.

Preparation of Cell Homogenate
Isolated cells from each donor were suspended to a concentration of 2.5x10^-7 cells/mL in a phosphate-buffered saline consisting of 131 mmol/L NaCl and 10 mmol/L KH₂PO₄/K₂HPO₄ (pH 7.0). After the addition of protease inhibitors (15 µg/mL leupeptin, 50 ng/mL pepstatin, and 5 µg/mL APMSF), 10 µmol/L captopril, and 1 mmol/L EGTA, the cells were disrupted by sonification with three 15-second bursts and immersed in an ice-water bath using the microtip probe of a sonicator (Branson sonifier) set at low power.²² More than 95% of the cells were disrupted by this technique. Undisrupted cells, nuclei, and large debris were removed by centrifugation at 1000g for 10 minutes. The resultant supernatant was centrifuged at 100 000g for 30 minutes, and cytosolic fractions were obtained. Throughout all of these procedures, extreme care was taken to maintain the sample at <4°C.

Radioimmunoassay for Angiotensins I and II
The concentrations of angiotensins I and II were measured using radioimmunoassay (RIA) as described previously.²³ Briefly, the cytosolic fraction from each donor was diluted with RIA buffer (50 mmol/L Tris, pH 7.5) at three different concentrations, and anti-angiotensin antibody and ¹²⁵I-angiotensin were added to each diluted fraction. After overnight incubation at 4°C, polyethylene glycol (PEG 8000, 12.5%) was added to separate antibody-bound angiotensin and centrifuged at 10 000g for 45 minutes. Radioactivity of the pellet was measured using a gamma counter. Counts of the assay mixtures from three diluted fractions were fitted to the standard curve, and the average of three points was determined as a result from each donor. Protein concentration was measured by the method of Lowry et al.²⁴

Materials
Angiotensins I and II were obtained from Sigma Chemical Co. Anti-angiotensin I rabbit serum, anti-angiotensin II rabbit serum, and healthy rabbit serum were obtained from Peninsula Laboratories Inc. ¹²⁵I-Angiotensin I and ¹²⁵I-angiotensin II were obtained from New England Nuclear.

Statistical Analysis
The data are expressed as mean±SEM. An ANOVA followed by Schéffe's test was used for comparison of groups. P<.05 was considered to be significant.

	Results

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Immunocytochemistry for Angiotensins
We used two immunocytochemical approaches. Fig 1 shows fluorescence immunocytochemical findings for angiotensin in human mononuclear leukocytes. Positive immunostaining for angiotensin II was observed in the preparation of human mononuclear leukocytes (Fig 1A). Control experiments in which healthy rabbit serum was substituted for primary antibody showed no significant immunostaining (Fig 1B).

View larger version (90K): [in this window] [in a new window]   Figure 1. Fluorescence immunocytochemistry for angiotensin II in human mononuclear cells. These results were reproduced in monocytes from five individuals. Original magnification x2500. A, Angiotensin II antibody (1:200). B, Control serum (1:50).

We also performed light microscopy immunocytochemistry with an alkaline phosphatase method. As shown in Fig 2A, angiotensin II was distributed predominantly in large mononuclear leukocytes. Immunostaining for angiotensin I was also observed in mononuclear leukocytes, but the staining appeared to be less than staining for angiotensin II (Fig 2B). Control experiments in which healthy rabbit serum was substituted for primary antibody showed no significant immunostaining (Fig 2C). We performed another control experiment in which primary antibody was preadsorbed with standard angiotensin II. This control experiment also showed no significant immunostaining for angiotensin II (data not shown).

View larger version (0K): [in this window] [in a new window]   Figure 2. This and following page. Light microscopy immunocytochemistry for angiotensin II (A, 1:200) and I (B, 1:100) in human mononuclear cells. These results were reproduced in monocytes from five individuals. Original magnification x1000. C, Control serum (1:50).

Polymorphonuclear leukocytes showed some staining for angiotensin II, but the intensity appeared to be low (Fig 3A) without positive staining in control experiments (Fig 3B).

View larger version (0K): [in this window] [in a new window]   Figure 3. Light microscopy immunocytochemistry for angiotensin II in human polymorphonuclear cells. These results were reproduced in leukocytes from five individuals. Original magnification x1000. A, Angiotensin II antibody (1:200). B, Control serum (1:50).

Angiotensins in Cell Homogenate
We measured concentrations of angiotensins I and II in cell homogenates from both human mononuclear and polymorphonuclear leukocytes. The concentrations of angiotensins I and II in mononuclear leukocytes were 355±216 (mean±SEM) and 2331±106 fmol/mg protein, respectively (P<.05) (Fig 4). The concentrations of angiotensins I and II in polymorphonuclear leukocytes were 36±10 and 336±120 fmol/mg protein, respectively (P<.05) (Fig 4).

View larger version (10K): [in this window] [in a new window]   Figure 4. Bar graph reflecting angiotensins in cell homogenate. Isolated mononuclear cells (MONO) and polymorphonuclear cells (PMN) from each donor were disrupted by sonification. After centrifugation, the supernatants of both cell suspensions were collected. Amounts of angiotensin I (AI) and II (AII) were measured using radioimmunoassay. Values represent mean±SEM of the results from six donors.

	Discussion

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The major new finding of the present study is that human mononuclear leukocytes contain substantial quantities of angiotensins I and II. The amount of angiotensin II is much greater than that of angiotensin I in human mononuclear leukocytes. The concentration of angiotensin II is much larger in monocytes than in polymorphonuclear leukocytes.

Presence of Angiotensin II in Monocytes
We used two different immunocytochemical techniques to demonstrate angiotensin II in human monocytes. Fluorescence immunocytochemical findings indicate that angiotensin II may be present primarily in mononuclear leukocytes. An alkaline phosphatase method showed strong signals for angiotensin II in mononuclear leukocytes. With this method, the size and shape of the nucleus are well defined. Large cells with kidney-shaped nuclei demonstrated marked staining, which suggests that monocytes contain angiotensin II. The cytoplasm of each monocyte showed granular staining, suggesting that some granules may contain angiotensin II. Immunocytochemistry with electron microscopy will be required to define the subcellular localization of this peptide.

Cell homogenate from human mononuclear leukocytes contains a considerable amount of angiotensin II. Relative to mononuclear leukocytes, human polymorphonuclear leukocytes do not contain much angiotensin. A preliminary report¹⁹ suggested that cell homogenates from human leukocytes have more angiotensin I than angiotensin II. The present findings suggest that angiotensin II is the predominant peptide in human mononuclear and polymorphonuclear leukocytes. Although we used a cocktail of three protease inhibitors and 1 mmol/L EGTA to prevent conversion of angiotensinogen and angiotensin I to angiotensin II during preparation of homogenate, we cannot exclude the possibility that activated proteases from leukocytes cleaved angiotensin I to form angiotensin II.²⁵ Our immunocytochemical findings, however, support strongly the findings with RIA. Thus, our findings suggest that the predominant peptide in human mononuclear leukocytes is angiotensin II. Because the antibody against angiotensin II used in the present study cross-reacts completely with angiotensin III, we cannot exclude the possibility that angiotensin III may be present in human mononuclear leukocytes.

Gomez et al⁷ demonstrated mRNA of angiotensinogen in rat mononuclear leukocytes by using a Northern blot analysis. They have also shown that angiotensinogen, but not angiotensin I or angiotensin II, is released from rat mononuclear leukocytes in a constitutive manner. Thus, mononuclear leukocytes appear to be capable of delivering angiotensinogen to tissues. In the present study, we have shown that human monocytes contain angiotensin II. It is not known whether angiotensin II in monocytes is converted from angiotensinogen intracellularly or is taken up from blood. Monocytes contain cathepsin G, which can cleave angiotensinogen to produce angiotensin II directly.^{8 9 10} In addition, monocytes and macrophages have receptors for angiotensin II.^{26 27} When angiotensin II binds to its receptors on monocytes, endocytosis occurs and angiotensin II is taken up by monocytes.²⁶ Thus, both synthesis and uptake of angiotensin II are possible in monocytes.

Study Implications
Angiotensin II has mitogenic effects on vascular muscle^{28 29} and a chemotactic effect on monocytes and macrophages.^{30 31 32 33} The finding that angiotensin-converting enzyme inhibitors attenuate atherosclerosis in some hypercholesterolemic animal models^{12 13} suggests a role for the renin-angiotensin system in atherogenesis. Thus, we speculate that angiotensin II that is derived from monocytes may play an important role in atherogenesis.^{34 35}

Activation of the renin-angiotensin system may contribute to the development of vascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP).¹⁴ Inhibition of the renin-angiotensin system by low concentrations of angiotensin-converting enzyme inhibitors, which does not decrease blood pressure, reduces arterial lesions in salt-loaded SHRSP^{36 37} and in malignant hypertension in SHRSP.³⁸ Monocytes have been observed to infiltrate the subendothelial space of blood vessels, and they may contribute to endothelial dysfunction during hypertension.^{15 16} Macrophages in granulomas also contain and release angiotensins.^{17 18} We speculate that release of angiotensin II from monocytes and/or macrophages may contribute to the arterial lesions during chronic hypertension.

View larger version (0K): [in this window] [in a new window]   Figure 2B. Continued.

	Acknowledgments

 
We thank Ms Donna Farley for assay of angiotensin I and II, Dr Frank M. Faraci for critical review of the manuscript, Mr Robert M. Brooks II for isolation of leukocytes, and Ms Arlinda LaRose for secretarial assistance.

Received June 30, 1994; accepted September 20, 1994.

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