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(Hypertension. 1996;27:823-826.)
© 1996 American Heart Association, Inc.

Articles

Nitric Oxide Induces Upregulation of Fas and Apoptosis in Vascular Smooth Muscle

Keisuke Fukuo; Shigeki Hata; Toshimitsu Suhara; Takeshi Nakahashi; Yoshitaka Shinto; Yoshihide Tsujimoto; Shigeto Morimoto; Toshio Ogihara

From the Department of Geriatric Medicine (K.F., S.H., T.S., T.N., S.M., T.O.) and Department of Medical Genetics (Y.S., Y.T.), Biomedical Research Center, Osaka University Medical School, Osaka, Japan.

Correspondence to Keisuke Fukuo, MD, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan.

	Abstract

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Abstract Interleukin-1 induced a time-dependent release of high levels of nitric oxide from rat vascular smooth muscle cells up to 96 hours. A time-dependent release of lactate dehydrogenase was also induced by Interleukin-1 from 72 to 96 hours after its stimulation. In situ nick end-labeling assay revealed that incubation for 48 hours with interleukin-1 induced a positive staining of fragmented nuclei. However, N^G-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, inhibited both lactate dehydrogenase release and DNA fragmentation induced by interleukin-1. Furthermore, sodium nitroprusside, a nitric oxide donor, also induced lactate dehydrogenase release and DNA fragmentation. Fluorescent staining of DNA revealed patches of irregularly dispersed, brightly staining, and condensed chromatin in rat vascular smooth muscle cells treated with sodium nitroprusside. Flow cytometric analysis with monoclonal antibody against human Fas revealed that expression of Fas was upregulated by sodium nitroprusside in human vascular smooth muscle cells. Methylene blue, an inhibitor of soluble guanylate cyclase, did not affect sodium nitroprusside–induced upregulation of Fas. Furthermore, 8-bromo-guanosine 3':5'-cyclic monophosphate, an analogue of cGMP, did not upregulate Fas expression. These findings indicate that nitric oxide released from vascular smooth muscle cells may induce apoptosis in vascular smooth muscle cells themselves and also induces upregulation of Fas via a cGMP-independent mechanism. Thus, nitric oxide could trigger the remodeling of atherosclerotic plaques.

Key Words: nitric oxide • Fas antigen • apoptosis • muscle, smooth, vascular

	Introduction

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Nitric oxide is a multifunctional molecule that mediates a number of diverse physiological processes.¹ There is recent evidence that IL-1, a macrophage-derived cytokine, stimulates the release of large amounts of NO from VSMCs in vitro.² Furthermore, diet-induced atherosclerosis increases the release of NO from rabbit aorta,³ and vascular smooth muscle contains a system that generates NO after balloon injury in vivo.⁴ However, pathophysiological roles of this NO released from VSMCs have not been defined. Since NO is known to exert various toxic effects on many cell types,^{5 6} we considered the possibility that NO may be a mediator of vascular damage during the development of atherosclerotic lesions. Thus, we first examined whether NO released from VSMCs induces cell death in VSMCs themselves.

Fas is a type 1 membrane protein belonging to the tumor necrosis factor receptor family, which mediates death signal.⁷ Triggering this pathway requires the cross-linking of Fas either with antibodies to Fas or with cells expressing Fas ligand. Various cells express Fas, whereas Fas ligand is expressed predominantly in activated T cells. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune disease, whereas its exacerbation may cause tissue destruction.⁷

Therefore, we next examined whether NO can affect Fas expression in VSMCs.

	Methods

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Materials
Human recombinant IL-1ß was donated by Otsuka Pharmaceutical Co. L-NMMA, SNP, and 8-Br-cGMP were purchased from Sigma Chemical Co. NOC-18 was from Dojin Laboratory. Monoclonal antibody to human Fas (IgG, clone UB2) was from Medical Biological Laboratories. Fluorescein isothiocyanate–labeled goat anti-mouse IgG was obtained from Seikagaku Kogyo. Hoechst 33258 was purchased from Flow Laboratories, Inc.

Cell Culture
VSMCs were isolated from rat aortas or human aortas and saphenous vein as described previously.⁸ After reaching confluence, VSMCs were preincubated for 48 hours with serum-free Dulbecco's modified Eagle's medium containing 0.1% bovine serum albumin to become quiescent before the experiments. Fas-expressing NIH 3T3 cells, in which the 2.6-kb Xho I fragment containing Fas cDNA was stably transfected, were generously provided by Dr Shigekazu Nagata (Osaka Bioscience Institute, Osaka, Japan).

Nitrite Assay
We measured the level of nitrite in the medium as a reflection of NO production by using Griess reagent as described previously.⁸

LDH Assay
LDH activity in cell-free supernatant was measured with a commercial kit (Sigma Chemical Co), as described previously.⁸ Total LDH activity was determined from the supernatant of a sample of incubated VSMCs with 0.1% Triton X-100 for 30 minutes.

In Situ Nick End-Labeling Assay and Nuclear Staining of Apoptotic Cells
VSMCs were cultured on tissue culture chamber slides (Nunc Inc) to analyze nuclear morphologies. The method for nick end-labeling of apoptotic cells was adapted from Gavrieli et al⁹ with a commercial kit (Oncor Inc). It is based on the preferential binding of digoxigenin-dUTP by terminal deoxynucleotidyl transferase to 3'-OH ends of DNA. The anti-digoxigenin antibody fragment carries a conjugated peroxidase to the reaction site. The localized peroxidase enzyme then catalytically generates an intense signal from chromogenic substrates. To analyze fragmented apoptotic nuclei, VSMCs were fixed with methanol/acetic acid, 3:1 (vol/vol), and stained with fluorescent dye (Hoechst 33258, 10 µmol/L). Photographs were obtained with a Nikon EFD2 fluorescence microscope (x400).

Expression of Fas in Human VSMCs
VSMCs (10⁶) were stained first with 1 µg of the murine antibody against human Fas and then with a fluorescein isothiocyanate–conjugated goat antibody to murine IgG (Wako Pure Chemical Industries Ltd). Fas expression on the cell surface was analyzed by FACScan (Becton Dickinson).

Statistical Analysis
Statistical analysis was performed by one-way ANOVA after a post hoc test. Results are expressed as mean±SEM. A value of P<.05 was considered significant.

	Results

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Fig 1 shows the kinetics of NO and LDH release from VSMCs after exposure to 1 nmol/L IL-1. IL-1 induced a time-dependent release of high levels of NO from VSMCs. IL-1 also induced a significant release of LDH time-dependently from 72 to 96 hours after its stimulation. On the other hand, 3 mmol/L L-NMMA, an inhibitor of NO synthase, inhibited both NO and LDH release induced by IL-1. Furthermore, incubation for more than 72 hours with 0.5 mmol/L SNP, an NO donor, also induced LDH release from VSMCs.

View larger version (19K): [in this window] [in a new window]   Figure 1. Nitric oxide–induced cell death in rat VSMCs. Quiescent rat VSMCs were incubated for the indicated times with serum-free medium containing 0.5 mmol/L SNP or 1 nmol/L IL-1 in the presence or absence of 3 mmol/L L-NMMA. Nitrite concentration (A) and LDH activity (B) in the medium were determined as described in the text. Values are mean±SEM of four individual experiments containing three replicates in each experiment. *P<.05, significantly different from control; **P<.05, significantly different from cells treated with IL-1 alone.

We next examined whether NO induces apoptosis in VSMCs. In situ nick end-labeling assay revealed that incubation for 48 hours with IL-1 induced a positive staining of fragmented nuclei in VSMCs (Fig 2). However, L-NMMA inhibited IL-1–induced DNA fragmentation. Furthermore, SNP also induced DNA fragmentation in VSMCs. Fig 3 shows nuclear morphology of VSMCs after incubation for 48 hours with 0.5 mmol/L SNP. Fluorescent staining of DNA revealed patches of irregularly dispersed, brightly staining, and condensed chromatin. Chromosome spreads of apoptotic nuclei stained homogeneously, indicating a loss of normal nuclear structure and characteristic features of apoptosis.

View larger version (103K): [in this window] [in a new window]   Figure 2. Apoptotic features of NO-induced cell death. Quiescent VSMCs were incubated for 48 hours with 0.5 mmol/L SNP or 1 nmol/L IL-1 in the presence or absence of 3 mmol/L L-NMMA. After the incubation, cells were fixed and stained by the method of in situ nick end-labeling as described in the text. The figure shows one representative experiment out of three.

View larger version (101K): [in this window] [in a new window]   Figure 3. Nuclear morphology of rat VSMCs. Quiescent rat VSMCs were incubated for 48 hours with 0.5 mmol/L SNP or vehicle. Cells were then stained with Hoechst 33258 (10 µmol/L) as described in the text. The figure shown represents one of three independent experiments.

Next, we examined whether NO can affect the expression of Fas, a death signal in VSMCs. As shown in Fig 4, incubation for 48 hours with 0.5 mmol/L SNP induced an increase in Fas expression in VSMCs. NOC-18 (0.5 mg/mL), a less toxic NO-releasing compound than SNP, also increased Fas expression in VSMCs. However, 2 mmol/L 8-Br-cGMP did not affect Fas expression. Furthermore, 100 µmol/L methylene blue, an inhibitor of soluble guanylate cyclase, did not inhibit SNP-induced Fas expression.

View larger version (26K): [in this window] [in a new window]   Figure 4. NO induces upregulation of Fas antigen in human VSMCs. Quiescent human VSMCs were treated for 48 hours with 0.5 mmol/L SNP in the presence or absence of 100 µmol/L methylene blue, 0.5 mg/mL NOC-18, or 2 mmol/L 8-Br-cGMP. Fas antigen expression was then analyzed by a flow cytometer as described in the text. Histograms obtained by each treatment are shaded. Data shown represent one of three independent experiments.

	Discussion

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Although much attention has been paid to the proliferation of VSMCs in the pathogenesis of atherosclerosis, not only proliferation of VSMCs but also cell necrosis is found in atherosclerotic plaques.^{10 11} Furthermore, rupture of the plaque into this necrotic area has been suggested to play an important role in the pathogenesis of arterial infarction.¹² Recently, Bennett et al¹³ reported that VSMCs isolated from atherosclerotic plaques have a markedly elevated rate of apoptosis in vitro. We have also demonstrated that high levels of NO released from VSMCs induce VSMC death, which results in release of basic fibroblast growth factor, which then stimulates adjacent endothelial cell proliferation.⁸

In the present study, we demonstrate that NO released from VSMCs induced apoptotic cell death in VSMCs themselves. There is recent evidence that NO also induces apoptosis in macrophages.¹⁴ Although the precise mechanism of NO-induced apoptosis is not known, Nguyen et al¹⁵ reported that NO can deaminate purine and pyrimidine bases in DNA and result in increased mutagenesis and in DNA strand breaks.

In the present study, we also demonstrate for the first time that NO upregulates Fas expression in VSMCs. SNP, an NO donor, induced an upregulation of Fas in human VSMCs. Although NO activates soluble guanylate cyclase, generating cGMP, 8-Br-cGMP, an analogue of cGMP, did not affect Fas expression. Furthermore, methylene blue did not inhibit SNP-induced Fas expression, suggesting that NO induces upregulation of Fas expression via a cGMP-independent mechanism. There is recent evidence that NO inhibited NF-B by stabilization of IB through a cGMP-independent mechanism.¹⁶ NO is also reported to induce inactivation of protein kinase C activity by direct modification of the enzyme involving the formation of disulfide bridges.¹⁷ NOC-18 is a newly developed NO-releasing compound that releases NO in solution without producing toxic metabolites.¹⁸ Since NOC-18 does not release cyanide, it is unlikely that cyanide is responsible for the upregulation of Fas expression. However, peroxynitrite or some unidentified mediator released during the incubation with NO donors or IL-1 might be involved in the upregulation of Fas expression in VSMCs. Further studies are needed to clarify these points.

Triggering Fas-mediated pathways requires the cross-linking of Fas either with antibodies to Fas or with cells expressing Fas ligand. Various cells express Fas, whereas Fas ligand is expressed predominantly in activated T cells.⁷ Since T cells are known to coexist with macrophages and VSMCs in the atherosclerotic plaque, Fas could mediate death signal by cross-linking with Fas ligand expressed in activated T cells. Necrotic cell death is a pathological pathway that leads to uncontrolled cellular homeostasis. On the other hand, apoptosis is a physiological suicide pathway to maintain tissue homeostasis. However, overexpression of Fas may induce massive apoptosis, which could lead to tissue destruction, such as plaque rupture.

In conclusion, NO released from VSMCs induced apoptosis in VSMCs themselves and upregulation of Fas expression in VSMCs. Thus, NO released from VSMCs could trigger the remodeling of atherosclerotic plaques.

	Selected Abbreviations and Acronyms

 

8-Br-cGMP = 8-bromo-guanosine 3':5'-cyclic monophosphate IL-1 = interleukin-1 L-NMMA = NG-monomethyl-L-arginine LDH = lactate dehydrogenase NO = nitric oxide NOC-18 = (CH2)2NH2N[N(O)NO]-(CH2)2NH2+H SNP = sodium nitroprusside VSMC = vascular smooth muscle cell

	Acknowledgments

 
This work was supported by grants from the Ministry of Education, Science, and Culture of Japan and from Sandoz Foundation for Gerontological Research. We thank Taeko Kaimoto for her technical and Tomoko Adachi for her secretarial assistance.

	References

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