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CARDIOVASCULAR

Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc

Life Science and Bioethics Research Center (C.K., A.K., M.Y.) and Geriatrics and Vascular Medicine (A.K.), Tokyo Medical and Dental University, Tokyo, Japan; and Department of Medicine IV, Tokyo Women's Medical University, Tokyo, Japan (C.K., T.T., K.N.)

Received July 2, 2007; accepted September 17, 2007.

	Abstract

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To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC) in THP-1 cells, resulting in the up-regulation of 4 and 2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.

ACEIs also have unique beneficial effects on atherosclerosis that are independent of Ang II. For instance, bradykinin-NO system played an important role in the beneficial effects of imidapril on vascular remodeling (Chen et al., 2003). Enalapril reduced atherosclerosis by up-regulation of peroxisome proliferator-activated receptor- and - in apolipoprotein E-deficient mouse (da Cunha et al., 2005). Ramiprilat/ramipril increased cyclooxygenase-2 expression and inhibited vasodilator prostanoid reduction (Kohlstedt et al., 2005).

Recently, AbdAlla et al. (2004) reported that ACE-dependent Ang II generation is involved in the factor XIIIA-cross-linked angiotensin II receptor 1 (AT1 receptor) dimers on monocytes of hypertensive patients. Moreover, ACE inhibition significantly decreased monocyte adhesion.

The adhesion of peripheral monocytes to vascular endothelium is one of the crucial steps in atherosclerosis. Monocyte-endothelial interaction consists of well organized sequential events, such as rolling, adhesion, and transmigrations (Butcher, 1991). Monocyte chemoattractant protein (MCP)-1, an inflammatory chemokine, plays a distinct role in these processes (Gerszten et al., 1999). MCP-1 stimulates monocyte recruitment to the site of injury via activation of integrins and thus promotes migration into the vessel wall (Reape and Groot, 1999; Libby, 2000). We previously confirmed that MCP-1 enhances monocyte-endothelial cell adhesion under flow condition (Hiraoka et al., 2004).

Recent advances have led to a better understanding of the effectiveness of ACEIs in monocyte adhesion; however, the molecular mechanisms that regulate monocyte adhesion are not fully elucidated. In the present study, we demonstrated that imidaprilat, an active metabolite of imidapril, attenuated MCP-1-triggered monocyte-endothelial interaction.

	Materials and Methods

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Reagent. Imidaprilat, (4S)-3-[(2S)-N-[(1S)-1-carboxy-3-phenylpropyl]alanyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid was kindly provided by Tanabe Seiyaku Company (Tokyo, Japan). The reagents and antibodies used in the present study are as follows: captopril, (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid, and calphostin C (Calbiochem, San Diego, CA); phorbol 12-myristate 13-acetate (PMA), ZnSO₄ ·7H₂O, and sodium pyrithione (Wako Pure Chemicals, Tokyo, Japan); N,N,N', N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) and 4'-6-diamidino-2-pheny-lindole (Dojindo Laboratories, Kumamoto, Japan); Alexa 488-conjugated anti-mouse IgG and FluoZin-3 acetoxymethyl ester (Invitrogen, Carlsbad, CA); and MCP-1 and tumor necrosis factor- (R&D Systems, Minneapolis, MN). RPMI 1640 medium and Dulbecco's phosphate-buffered saline were from Sigma-Aldrich (St. Louis, MO), anti-2 integrin (clone 7A10) was a generous gift from The Scripps Research Institute (La Jolla, CA), anti-4 integrin was from Upstate Biotechnology (Charlottesville, VA), ACE (clone 9B9) was from Chemicon International (Temecula, CA), anti protein kinase C (PKC) and - were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).

Cell Culture. THP-1, a human monocytic cell line, was obtained from American Type Culture Collection (Manassas, VA), and cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 100 IU/ml penicillin, 100 µg/ml streptomycin, and 2 mM L-glutamine in a humidified atmosphere of 5% CO₂ at 37°C. HUVECs were purchased from Sanko Junyaku (Tokyo, Japan). For use in the flow-chamber apparatus, human umbilical vein endothelial cells (HUVECs) were placed onto 22-mm fibronectin-coated glass coverslips. To examine cell viability, THP-1 cells were stained with a 0.3% trypan blue solution and 4'-6-diamidino-2-phenylindole solution after incubation with imidaprilat, TPEN, or ZnSO₄/pyrithione.

Monocyte Preparation. Monocytes were freshly isolated from a buffy coat, using a MACS monocyte isolation kit II (Miltenyi Biotec, Inc., Auburn, CA). Isolated monocytes were cultured in media containing 20% AB human serum (The Interstate Companies, Bloomington, MN), 10 ng/ml macrophage–colony-stimulating factor (Genzyme Techne, Minneapolis, MN), 100 IU/ml penicillin, and 100 µg/ml streptomycin in RPMI 1640 medium.

Monocyte Adhesion Assay. The protocols of the adhesion assay under flow conditions have been described in detail previously (Yoshida et al., 2001). In brief, HUVEC monolayers were stimulated with 5 ng/ml tumor necrosis factor- for 4 h on coverslips and then positioned in a flow chamber mounted on an inverted microscope (Nikon, Tokyo, Japan). Monocytes and THP-1 cells (1 x 10⁶/ml) were incubated in the presence or absence of the indicated concentration of imidaprilat for the indicated period. After resuspending with perfusion medium (PBS containing 0.2% human serum albumin) were perfused drawn through the chamber with a syringe pump (PHD2000; Harvard Apparatus Inc., Holliston, MA) for 10 min at a controlled flow rate to generate a shear stress of 1.0 dyne/cm². In some experiments, the cells were treated with MCP-1 (100 ng/ml; 10 min) or PMA (250 nM; 10 min) just before the assay. The entire period of perfusion was recorded by videotape and then transferred to a personal computer for image analysis to determine the number of rolling and adherent cells on HUVEC monolayers in 10 randomly selected 20x microscope fields.

Flow Cytometric Analysis. THP-1 cells were washed with RPMI 1640 medium containing 5% FCS, and then they were incubated with each primary antibody (1:300 dilution), followed by incubation with Alexa 488-conjugated goat anti-mouse antibody (1:250 dilution). Fluorescence intensity was analyzed using a FACScalibur (BD Biosciences, San Jose, CA).

Flow cytometric measurement of labile zinc was performed as described previously (Haase et al., 2006). THP-1 cells (1 x 10⁶/ml) were loaded with FluoZin-3 acetoxymethyl ester (1 µM) in RPMI 1640 medium with 1% FCS at 37°C for 30 min, washed with PBS, and then resuspended in PBS supplemented with 10% FCS. Aliquots of the cells were incubated with TPEN, zinc/pyrithione, MCP-1, and PMA at 37°C for 10 or 30 min as described figures.

Immunoblotting. Total cell lysates and membrane fraction of THP-1 cells (1 x 10⁶/condition) were prepared as described previously (Yoshida et al., 2001). Lysates from each fraction was subjected to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Western blotting analysis was carried out with antibodies as described above.

ACE Activity Assay. THP-1 cells (5 x 10⁵/condition) were washed with PBS and resuspended in lysis buffer containing 1% Triton X-100 in PHEM buffer, and then they were centrifuged to recover the clear cell lysate. ACE activity was measured by using ACE activity assay kit (Life Laboratory Company, Yamagata, Japan) following the manufacturer's protocol.

Statistical Analysis. Results are presented as mean ± S.E.M. Data were analyzed using one-way analysis of variance with Turkey's post hoc analysis. A P value less than 0.05 was considered statistically significant.

	Results

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Imidaprilat Attenuates MCP-1-Triggered Monocyte Adhesion to Vascular Endothelium. We examined the effect of imidaprilat on monocyte-endothelial interactions under flow conditions (shear stress of 1.0 dyne/cm²). MCP-1 increased THP-1 cell adhesion to activated HUVECs (pre-MCP-1, 6.4 ± 0.8/HPF; post-MCP-1, 12.6 ± 0.8/HPF; P < 0.001). Preincubation of THP-1 cells with imidaprilat reduced their adhesion (50–500 nM; 4 h) (Fig. 1A). As shown in Fig. 1B, the effect of imidaprilat was observed as early as 4 h after treatment. Therefore, we incubated THP-1 cells with imidaprilat at 50 nM for 4 h in the subsequent experiments. Imidaprilat also inhibited the adhesion of freshly isolated monocytes stimulated with MCP-1 (Fig. 1C). Imidaprilat did not affect THP-1 cell adhesion in the absence of MCP-1 stimulation (data not shown).

View larger version (13K): [in this window] [in a new window]   Fig. 1. Imidaprilat significantly reduced the number of MCP-1-triggered monocyte adhesion. THP-1 cells (A and B) and monocytes (C) were incubated at 37°C in the presence of the indicated concentrations of imidaprilat for the indicated period, followed by stimulation with MCP-1 (100 ng/ml) for 10 min before the assay. Adhesion assay was carried out as described under Materials and Methods. Data are representative of three independent experiments. A, ***, P < 0.001 versus control; , P < 0.01 versus MCP-1. B, ***, P < 0.001 versus control; , P < 0.05 versus MCP-1; , P < 0.01 versus MCP-1. C, *, P < 0.05 versus control; , P < 0.05 versus MCP-1.

View larger version (16K): [in this window] [in a new window]   Fig. 2. A and B, effects of imidaprilat on integrin expression in THP-1 cells. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by incubation with MCP-1 (100 ng/ml; 10 min) or medium alone (control). The expressions of 4 integrin (A) and 2 integrin (B) were analyzed by flow cytometric analysis as described under Materials and Methods. Data are representative of three independent experiments.

Imidaprilat Attenuates PMA-Triggered Monocyte Adhesion to Vascular Endothelium by Inhibiting PKC Activation. PKC plays an important role in monocyte-endothelial interaction. We tried to elucidate the intracellular mechanisms responsible for this phenomenon. MCP-1 activated PKC but not PKC, which were reduced by imidaprilat treatment (Fig. 3A).

View larger version (18K): [in this window] [in a new window]   Fig. 3. A, imidaprilat attenuated MCP-1-induced PKC activation in THP-1 cells. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by stimulation with MCP-1 (100 ng/ml) for 10 min before the assay, and the membrane and total PKC and - protein were detected with immunoblotting (IB). Data were representative of three independent experiments. B, imidaprilat attenuated PMA-induced PKC and - activation in THP-1 cells. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by stimulation with PMA (250 nM) for 10 min before the assay and the membrane and total PKC and - protein was detected with IB. Data are representative of three independent experiments. C and D, imidaprilat significantly reduced the number of PMA-triggered monocyte adhesion. THP-1 cells (C) and monocytes (D) were pretreated with imidaprilat (50 nM) for 4 h, followed by stimulation with PMA (250 nM) for 10 min before the assay. Adhesion assay was carried out as described under Materials and Methods. Data were representative of three independent experiments. ***, P < 0.001 versus control; , P < 0.01 versus PMA; , P < 0.001 versus PMA.

Expression Level of ACE Is Not Significantly Changed after PMA or MCP-1 Treatment. Since ACE expression on monocytes may contribute to vascular inflammation such as monocyte-endothelial adhesion through local renin angiotensin system activation (Metzger et al., 2000), we next examined the expression levels of ACE in THP-1 cells. As shown in Fig. 4, MCP-1 (Fig. 4, A and C) or PMA (Fig. 4, B and D) failed to change ACE expression. We also found that ACE activity was not changed after MCP-1 or PMA treatment in THP-1 cells (data not shown).

View larger version (16K): [in this window] [in a new window]   Fig. 4. ACE expression levels were not altered before and after MCP-1 or PMA treatment. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by stimulation with MCP-1 (A and C) or PMA (B and D) for 10 min. The expression level of ACE was detected using flow cytometric analysis (A and B) and immunoblotting (C and D) as described under Materials and Methods. Data were a representative of three independent experiments.

Imidaprilat Modulates MCP-1 or PMA-Induced Elevation of Labile Zinc in THP-1 Cells. Next, we focused on the effect of ACEIs on labile (i.e., free or loosely bound) zinc, since ACEIs have been shown to decrease intracellular zinc concentration (Golik et al., 1998), and zinc has the potential to regulate cellular function, including PKC activation (Csermely et al., 1988; Zalewski et al., 1990). We first measured labile zinc using a zinc-sensitive fluorescent probe, FluoZin-3. Indeed, FluoZin-3-associated fluorescence intensity increased after zinc/pyrithione (zinc ionophore) treatment, which was decreased by incubation with TPEN (zinc chelator) (Fig. 5A).

View larger version (16K): [in this window] [in a new window]   Fig. 5. Flow cytometric measurement of labile zinc in THP-1 cells. A, THP-1 cells were loaded with FluoZin-3 as described under Materials and Methods, and zinc-related fluorescence activity was measured using flow cytometer after 30 min of incubation with 10 µM ZnSO4/50 µM pyrithione (black line), 50 µM TPEN (hatched line), or medium alone (shaded area). B, fluorescence intensity of FluoZin-3-loaded THP-1 stimulated with MCP-1 (100 ng/ml) for 10 min (black lines), imidaprilat (50 nM; 4 h) and MCP-1 (100 ng/ml; 10 min) (hatched lines), or medium alone (shaded area). C, fluorescence intensity of FluoZin-3-loaded THP-1 cells stimulated with PMA (250 nM) for 10 min (black lines), imidaprilat (50 nM; 4 h) and PMA (hatched lines), or medium alone (shaded area). Data are representative of three independent experiments.

Imidaprilat Attenuates Zinc-Induced THP-1 Cell Adhesion via Reduction of PKC Activation. Imidaprilat inhibited zinc/pyrithione-induced elevation of labile zinc (Fig. 6A). Captopril also diminished zinc/pyrithione-induced an increase of labile zinc (Supplemental Fig. S2). When monocytes were treated with zinc/pyrithione to increase labile zinc, monocyte adhesion to activated HUVECs significantly increased comparable with PMA treatment (Fig. 6B). Furthermore, zinc/pyrithione-induced THP-1 cell adhesion was reduced by treatment with TPEN or imidaprilat. Calphostin C, a PKC inhibitor, also inhibited zinc/pyrithione-induced THP-1 cell adhesion (Fig. 6C). Indeed, zinc/pyrithione treatment activated PKC and -, which was reduced by imidaprilat treatment (Fig. 6D).

View larger version (19K): [in this window] [in a new window]   Fig. 6. A, imidaprilat reduced zinc/pyrithione-induced elevation of labile zinc. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by stimulation with ZnSO4 10 µM/pyrithione 50 µM for 30 min before the assay. B, zinc/pyrithione induced monocyte adhesion to HUVECs. Monocytes were stimulated with 10 µM ZnSO4/50 µM pyrithione for 30 min or PMA (250 nM) for 10 min, and their adhesion to HUVECs was examined under flow conditions. **, P < 0.01 versus control. C, THP-1 cells were incubated in the presence of imidaprilat (50 nM; 4 h), TPEN (50 µM; 30 min), or calphostin C (500 nM; 30 min) followed by stimulation with 10 µM ZnSO4/50 µM pyrithione for 30 min before the assay. Their adhesion to HUVECs was then examined under flow conditions. **, P < 0.01 versus control; , P < 0.05 versus zinc/pyrithione D, imidaprilat reduced zinc/pyrithione-induced PKC activation in THP-1 cells. THP-1 cells were incubated in the presence or absence of imidaprilat (50 nM) for 4 h, followed by stimulation with 10 µM ZnSO4/50 µM pyrithione for 30 min before the assay, and the membrane and total PKC and - protein were detected with IB.

	Discussion

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Increased ACE expression is observed in atherosclerotic lesions (Fukuhara et al., 2000). ACE expression on monocyte-derived cells may contribute to local renin angiotensin system activation at sites of vascular wall and subsequent progression of the atherosclerotic plaque (Metzger et al., 2000). Although PMA treatment increases ACE activity and ACE mRNA levels in HUVECs and medium (Villard et al., 1998), MCP-1 and PMA did not significantly alter ACE enzymatic activity in our condition. PMA has been shown to cleave cell surface ACE in HUVECs (Chattopadhyay et al., 2005), we examined the presence of ACE in THP-1 cells before and after treatment with PMA as shown in Fig. 4. Moreover, PMA treatment did not increase the amount of ACE in culture medium (data not shown). These results suggest that other properties of ACEIs may affect MCP-1 or PMA-induced THP-1 cell adhesion in addition to inhibit ACE activity.

ACE, as is the case with other family of metalloenzyme, has the zinc ion at its active site, and ACEIs are designed to block this zinc cofactor domain of ACE (Cushman and Ondetti, 1999). This urged us to examine a potential contribution of labile zinc in adhesive interactions of THP-1 cells. First, we demonstrated that MCP-1 and PMA as well as excessive zinc triggered an increase in labile zinc in THP-1 cells. Second, imidaprilat inhibited the observed elevation of labile zinc (Figs. 5 and 6). Previous studies revealed that transitional metals such as zinc play a critical role in regulation of various aspects of biological events in animals (Beyersmann and Haase, 2001). Indeed, zinc is also associated with the activity of various catalytic enzymes, including PKC and matrix metalloproteinase, as well as ACE. Therefore, both depletion and excess of labile zinc are associated with pathophysiological conditions. Intracellular zinc has been shown to be closely related to dendritic cell maturation and the regulation of MHC class II molecules (Kitamura et al., 2006). Zinc deficiency in mast cell prevented activation of PKC and nuclear factor B, resulting in reduction of cytokine production (Kabu et al., 2006). Previous studies reported that zinc treatment induces intercellular adhesion molecule-1 expression in endothelial cells (Martinotti et al., 1995) and leukocyte adhesion (Klein et al., 1994; Chavakis et al., 1999). Furthermore, a potential role of zinc in inflammatory signaling is proposed in monocytes (Haase and Rink, 2007).

We previously reported that PKC is one of key modulators of inflammatory process including cell adhesion (Kawakami et al., 2002; Yu et al., 2003; Takahashi et al., 2006). As mentioned, PKC contains cysteine-rich zinc finger motifs in the concerned domains. Zinc influences the activity and localization of PKC (Csermely et al., 1988; Zalewski et al., 1990). These data imply that elevation of intracellular zinc may cause inflammatory reaction through PKC activation. Indeed, Haase et al. (2006) reported that PMA treatment induced an increase of labile zinc in monocytes, which was suppressed by PKC inhibitor. Therefore, we hypothesized that modulating labile zinc by ACEI leads to inhibition of PKC activation. In line with previous studies, we confirmed that an increase in labile zinc induced by MCP-1 or PMA triggered PKC activation as well as monocyte adhesion. Imidaprilat pretreatment attenuated these processes. These results suggest the modulation of labile zinc and subsequent PKC inhibition as one of anti-inflammatory properties of an ACEI. The importance of labile zinc in other cell types and its modulation by ACEIs should be investigated in our future project.

In conclusion, ACEIs inhibit MCP-1 or PMA-triggered monocyte adhesion to activated endothelial cells. The underlying mechanisms seem to involve modulation of intracellular zinc in addition to their effects on ACE. Our findings may point a novel anti-inflammatory role for this compound.

	Acknowledgements

 
We thank Dr. Hideto Ishii for help in preparing the manuscript. We gratefully acknowledge the expert assistance of Daisuke Mori in working with the cell cultures.

	Footnotes

 
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.127944.

ABBREVIATIONS: ACE, angiotensin I-converting enzyme; Ang, angiotensin; ACEI, angiotensin I-converting enzyme inhibitor; MCP, monocyte chemoattractant protein; PMA, phorbol 12-myristate 13-acetate; TPEN, N, N, N', N'-tetrakis-(2-pyridylmethyl) ethylenediamine; PKC, protein kinase C; FCS, fetal calf serum; HUVEC, human umbilical vein endothelial cell; PBS, phosphate-buffered saline; IB, immunoblotting.

The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

Address correspondence to: Dr. Masayuki Yoshida, Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45 Yushima Bldg. D-9, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: masavasc{at}tmd.ac.jp

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