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(Hypertension. 2004;43:880.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Fas Signaling Induces Akt Activation and Upregulation of Endothelial Nitric Oxide Synthase Expression

Yukihiro Takemura; Keisuke Fukuo; Osamu Yasuda; Takahito Inoue; Norio Inomata; Toyohiko Yokoi; Hidenobu Kawamoto; Toshimitsu Suhara; Toshio Ogihara

From the Department of Geriatric Medicine (Y.T., O.Y., T.Y., H.K., T.S., T.O.), Osaka University Medical School, Japan; Department of Food Sciences and Nutrition (K.F.), School of Human Environmental Sciences, Mukogawa Women’s University, Nishinomiya, Hyogo, Japan; and Pharmaceutical Research Laboratories (T.I., N.I.), Suntory Institute for Biomedical Research, Mishima-gun, Osaka, Japan

Correspondence to Dr Keisuke Fukuo, Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women’s University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan. E-mail fukuo{at}mwu.mukogawa-u.ac.jp

	Abstract

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A growing body of evidence has shown that Fas, a death receptor, mediates apoptosis-unrelated biological effects. Here, we report that Fas engagement with Fas ligand induced activation of Akt and upregulation of endothelial nitric oxide synthase expression without induction of apoptosis. In the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin, Fas ligand, however, induced apoptosis instead of upregulation of endothelial nitric oxide synthase expression. In vivo, systolic blood pressure was slightly higher in mutant mice with decreased cell surface Fas expression (lpr mice) compared with wild-type mice. In addition, chronic inhibition of nitric oxide synthesis by N^G-nitro-l-arginine induced a progressive increase in the levels of blood pressure in wild-type mice, whereas no further increase in the levels of blood pressure was observed in lpr mice. Furthermore, acetylcholine caused a lesser endothelium-dependent relaxation of the strips from lpr mice compared with wild-type mice, although the vasoconstrictor potency of phenylephrine was not different between the two groups. These findings indicate that Fas signaling may have a role in the regulation of endothelial function and blood pressure through modulating endothelial nitric oxide synthase expression in the Akt signal-dependent manner.

Key Words: endothelial growth factors • nitric oxide synthase • hypertension

	Introduction

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Fas is a type I membrane receptor belonging to a member of the tumor necrosis factor (TNF) receptor superfamily. Activation of Fas by Fas ligand (FasL) induces apoptosis via activation of the caspase cascade.¹ Fas is expressed almost ubiquitously in a variety of cells, including endothelial cells (ECs). However, FasL is mainly expressed in immune cells such as natural killer cells, activated T cells, and macrophages, and also at some immune privileged sites, for example, eye and testis, where it is believed to protect those tissues by inducing apoptosis in Fas-bearing immune cells.^2,3 FasL, a member of TNF family, is rapidly cleaved off by a metalloproteinase from the membrane to become a soluble form (sFasL) as well as TNF-.⁴ In human studies, sFasL has been detected in the serum of patients with several cardiovascular diseases, for example, congestive heart failure and acute coronary syndromes.^5,6 Importantly, FasL is also expressed at low levels on the vascular endothelium. TNF-, an inflammatory cytokine, downregulates FasL expression in ECs, and overexpression of FasL on the endothelium attenuates leukocyte extravasations induced by TNF-.⁷ We also reported that sFasL released from ECs protect from hypoxia-induced apoptosis in ECs.⁸ Finally, EC overexpression of FasL attenuates ischemia-reperfusion injury in the heart.⁹ Collectively, these data suggest that FasL may play important roles in the maintenance of endothelial function.

Because many atherogenic factors can induce apoptosis in cultured ECs, Fas-mediated apoptosis leading to EC loss is thought to contribute to the pathogenesis of endothelial dysfunction and atherosclerosis.¹⁰ However, it has been well established that ECs are highly resistant to Fas-mediated apoptosis.¹¹ Interestingly, recent evidence has shown that Fas signaling can have apoptosis-unrelated biological effects, such as induction of neurite growth through activation of the extracellular signal-regulated kinase.¹² Fas engagement is also reported to induce cardiomyocyte hypertrophy instead of apoptotic cell death.¹³ However, it is not clear whether Fas signaling can induce apoptosis-unrelated effects in ECs.

Here, we show that Fas engagement induces an Akt-dependent upregulation of endothelial nitric oxide synthase (eNOS) expression in ECs, and that mutant mice with decreased cell surface Fas expression have hypertension with endothelial dysfunction.

	Methods

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Cell Culture and Reagents
Human umbilical vein ECs were purchased from Sanko Junyaku (Tokyo, Japan) and cultured in EBM-2 (Sanko Junyaku) supplemented with 2% FCS and antibiotics. Medium was replaced with fresh medium, with or without serum, typically at the time reagents were added. Recombinant FasL and the agonistic antibody to Fas (Jo2) were generously provided by Dr. Shigekazu Nagata (Osaka University). Wortmannin, N-nitro-L-arginine methyl ester (L-NAME), phenylephrine, and acetylcholine were purchased from Sigma. Anti-phospho-Akt and anti--tubulin antibodies were from Cell Signaling and Carbiochem, respectively.

Western Blot Analysis
Cells were washed with phosphate-buffered saline (PBS) twice and harvested by scraping. Cell lysates were prepared in cell lyses buffer (50 mmol/L Tris-HCl, pH 8.0, 20 mmol/L EDTA, 1% SDS, 100 mmol/L NaCl). Protein concentration was determined using the BioRad protein assay kit (Bio-Rad); 20 µg of protein extract was fractionated on SDS-polyacrylamide electrophoresis gel and transferred to a polyvinyldine diflouride membrane (Immobilon-P, Millipore). The membrane was blocked with T-PBS (1X PBS, 0.3% Tween 20) containing 3% dry milk and incubated with a primary antibody overnight at 4°C. After 3 washes with T-PBS, the membrane was incubated with a secondary antibody (anti-mouse or anti-goat IgG HRP conjugate [Promega]) for 1 hour, then washed with 0.05% Tween 20 in PBS. The immune complexes were detected by chemiluminescence methods (ECL, Amersham International).

Detection of Apoptosis by Annexin V Staining
Fluorescein isothiocyanate-labeled Annexin V (Fluos, Boehringer Mannheim) was used to bind exposed phosphatidylserine on cells undergoing the early stages of apoptosis. In brief, 10⁵ cells/mL were incubated with 1 mL Annexin V–fluorescein isothiocyanate of the provided solution for 30 minutes at room temperature and subsequently analyzed by FACSort (Becton Dickinson). Electronic compensation was used to eliminate spreading into adjacent fluorescence channels. Data analysis was performed with Cell Quest software.

Animal Experiments
Male MRL/MPJ^lpr/lpr mice and MRL/MPJ^+/+ mice were purchased from breeding colonies at Japan SLC (Shizuoka, Japan). Animal experiments were performed in 8-week-old to 10-week-old mice in accordance with the Ethics Committee on Animal Experiments and Care of the Osaka University.

Organ Culture
Thoracic aortas were collected from mice and were cultured in Dulbecco modified eagle medium (DMEM) with 10% FBS in the presence or absence of the agonistic antibody to Fas (Jo2) at a concentration of 1 µg/mL for 60 minutes at 37°C, 5% CO₂. The aortas were then washed in PBS and snap-frozen in OTC compound (Sakura, Tokyo). Serial 10-µm-thick cryostat sections were collected on poly-D-lysine-coated slides and fixed in acetone. Sections were immunostained using anti-CD31 monoclonal antibody (BD Bioscience) and anti-phospho-Akt antibody (Cell Signaling), respectively, followed by ABC method (Dako, Carpinteria, Calif).

Vascular Reactivity Studies
An aortic strip was prepared and placed in oxygenated modified Krebs-Henseleit solution. The strip was equilibrated for 60 minutes under resting tension of 1.0 g, which is optimal for inducing the maximal contraction in all vessels used. Relaxation response to acetylcholine was expressed as a percentage of decreased tension in contractile force induced by phenylephrine (3 mmol/L).

Measurement of Blood Pressure
Blood pressure was measured directly and indirectly. For direct measurements, we anesthetized mice with an intraperitoneal injection of pentobarbital sodium at 0.08 mg/g body weight. A femoral artery was cannulated with polyethylene tubing, after which the mouse was allowed to recover. To record blood pressure, the cannula was connected to a pressure transducer; arterial pressure was recorded continuously with mice conscious and unrestrained. For indirect measurements, blood pressure was measured without anesthesia using a programmable sphygmomanometer connected with a cuff probe for mouse (MCP-1, Softron). L-NAME was administrated in the drinking water at 1 mg/mL, whereas control animals (lpr and wild-type) received unmodified drinking water.

Statistical Analysis
Statistical analysis was performed by 1-way ANOVA after a post hoc test. Results are expressed as mean±SEM. A value of P<0.05 was considered significant.

	Results

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Fas Ligand Induces Upregulation of eNOS but not Apoptosis in ECs
As shown in the previous studies,¹ treatment with recombinant FasL induced apoptosis in Jurkat T lymphocytes and Fas-sensitive cells, but not in ECs or Fas-resistant cells (Figure 1A). FasL treatment, however, resulted in upregulation of eNOS expression in ECs after 24 hours without apoptosis induction (Figure 1B, 1C). Importantly, in the presence of the PI3 kinase inhibitor wortmannin, FasL induced apoptosis instead of upregulation of eNOS expression in ECs, indicating that the functional system of this apoptotic program in ECs was intact and that Fas-mediated eNOS expression may be Akt-dependent.

View larger version (26K): [in this window] [in a new window]   Figure 1. FasL induces upregulation of eNOS but not apoptosis in ECs. A, ECs or Jurkat T cells were treated with FasL (10 or 100 ng/mL) in the presence or absence of wortmannin (100 nmol/L) for 12 hours, and apoptosis was assessed by Annexin V staining as described in the text. Values are mean±SEM from 4 independent experiments. *P<0.05, significantly different from control. **P<0.05, significantly different from cells treated with FasL. B, ECs were treated with FasL (10 ng/mL) in the presence or absence of wortmannin (100 nmol/L). Lysates were prepared after 24 hours of incubation, and Western blot analyses of phospho-eNOS and -tubulin were performed on 20 µg of lysate. -Tubulin expression shows uniformity of protein loading in each line. C, Phospho-eNOS expression was quantified by densitometric analysis of Western blots from 4 independent experiments (data are normalized against -tubulin and expressed as mean±SEM). *P<0.05, significantly different from control.

FasL Induces Akt Phosphorylation in ECs
We next examined whether Fas engagement induces Akt activation in ECs. Incubation with FasL induced a transient increase in the levels of Akt phosphorylation, as did insulin in ECs (Figure 2A, B), whereas it did not induce an increase in the levels of Akt phosphorylation in Jurkat T lymphocytes (data not shown), indicating that the downstream signals of Fas may be different between these two cell types. Activation of the Akt signaling in ECs was observed from 5 minutes to 60 minutes after the stimulation with FasL. In addition, Fas engagement with the agonistic antibody Jo2 also induced Akt activation in aortic segments, suggesting that this activation can be induced in vivo (Figure 2C).

View larger version (46K): [in this window] [in a new window]   Figure 2. FasL induces Akt phosphorylation in ECs. A, ECs were treated with FasL (10 ng/mL) in the presence or absence of wortmannin (100 nmol/L). Lysates were prepared after the incubation, and phospho-Akt expression was analyzed by Western blotting. B, phospho-Akt expression was quantified by densitometric analysis as described in the legend of Figure 1. *P<0.05, significantly different from control. C, Thoracic aortas were collected from mice and were cultured with or without the agonistic antibody Jo2 (1 µg/mL) for 60 minutes, and sections of aortas were then stained for CD31, an EC marker, or phospho-Akt using ABC method (DAKO) as described in the text. Arrows indicate positive staining in the endothelium.

Hypertension Develops in Mutant lpr Mice but Progressive Hypertension Fails to Develop in Response to Long-Term NOS Inhibition
Because nitric oxide derived from eNOS is an important regulator of blood pressure,¹⁴ we next compared the blood pressure of lpr mice, which express decreased cell surface Fas, with wild-type mice. We found that systolic and diastolic blood pressures of lpr mice were significantly higher than those of wild-type mice, indicating that lpr mice are hypertensive (Figure 3A). To determine whether this elevation of blood pressure was related to diminished eNOS-derived nitric oxide production, we next examined the effect of L-NAME, an NOS inhibitor, on blood pressure in these mice. As shown in Figure 3B, chronic inhibition of NOS by L-NAME induced a progressive increase in blood pressure in wild-type mice but not in lpr mice.

View larger version (19K): [in this window] [in a new window]   Figure 3. Hypertension develops in mutant lpr mice, but chronic NOS inhibition induces no further increase in their blood pressure levels. A, Systolic and diastolic blood pressures of wild-type mice and lpr mice were measured as described in the text. Data are mean±SEM. *P<0.05, significantly different from corresponding wild-type mice; n=7 for wild-type mice; n=8 for lpr mice. B, Increases in blood pressure induced by administration of L-NAME. Blood pressure was measured by the tail-cuff method as described in the text. Data are mean±SEM. *P<0.05, significantly different from wild-type mice without L-NAME administration. **P<0.05, significantly different from wild-type mice with L-NAME administration; n=8 for both types of mice.

lpr Mice Have Impaired Endothelial Function
To determine the mechanism underlying systemic hypertension in Fas-lacking mice, we next examined the vascular responsiveness to phenylephrine and acetylcholine in Fas-lacking mice compared with wild-type mice. As shown in Figure 4A, the responsiveness to vasoconstrictor phenylephrine was not different between these two mice. In contrast, the endothelium-dependent relaxation induced by acetylcholine was significantly impaired in Fas-lacking mice compared with wild-type mice (Figure 4B). However, the endothelium-independent relaxation by a nitric oxide donor was not different between the groups (data not shown).

View larger version (16K): [in this window] [in a new window]   Figure 4. Differences between wild-type mice and lpr mice in response of aortic segments to phenylephrine and acetylcholine. A, Contractile responses to phenylephrine. Contractile responses of aortic segments with or without endothelium to phenylephrine were examined in wild-type and lpr mice. Data are normalized against K-induced contractile responses (n=8). B, Magnitudes of relaxation induced by acetylcholine are mean±SEM of percentage reversal of phenylephrine-induced contractile responses. *P<0.05, significantly different from wild-type mice (n=8).

	Discussion

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In the present study, we have shown that Fas activation induces Akt-dependent upregulation of eNOS expression in ECs. Reduced expression of Fas in vivo results in a development of hypertension. In addition, administration of the NOS inhibitor L-NAME fails to induce a further increase in the levels of blood pressure in mutant lpr mice with impairment of endothelial function. These findings imply that Fas signaling may have an important role in the pathogenesis of hypertension.

Recent evidence has shown that Fas signaling can mediate apoptosis-unrelated biological effects. For example, Fas activation induces T cell proliferation¹⁵ and activation of the prohypertrophic transcription factor AP-1 in cardiomyocytes rather than inducing apoptosis.¹⁶ In the present study, we have demonstrated that Fas engagement with FasL induces upregulation of eNOS expression instead of apoptosis in ECs. This is a first demonstration that Fas signaling can mediate an apoptosis-unrelated effect on ECs. Importantly, this effect is dependent on the survival signal Akt. In the presence of wortmannin, FasL did not induce upregulation of eNOS expression, but apoptosis in ECs and Fas signaling induced activation of Akt in ECs. These results are consistent with the recent report that Fas receptor signaling inhibits glycogen synthase kinase 3ß via phosphorylation by the upstream kinase Akt in cardiomyocytes.¹³ Notably, the PI3K/Akt signaling pathway is important in maintaining the expression of FLIP, an inhibitor of Fas-mediated death signaling.^17,18 In addition, this signaling pathway can mediate activation of eNOS, which induces upregulation of NO release from ECs.^19,20 Nitric oxide then activates the Akt signaling in ECs. Thus, the level of Akt activity appears to be critical to determine the directions of Fas signaling in terms of apoptosis-unrelated effects in ECs.

FasL, a member of TNF family, is shed by a metalloproteinase from the membrane to become sFasL as well as TNF-. We previously reported that FasL expression of circulating mononuclear cells is upregulated in patients with acute myocardial infarction, and that hypoxia stimulates the release of sFasL from these cells.⁶ The levels of sFasL released from ECs are also upregulated under hypoxia.⁸ In addition, sFasL released from peripheral blood mononuclear cells can induce apoptosis in keratinocytes,²¹ indicating that functional sFasL may be released from these FasL expressing cells, including ECs themselves. Although the levels of sFasL concentration in the circulation are lower compared with those in our studies, we assume that sFasL would mainly act locally on ECs as a paracrine factor, where its concentrations seem to be much higher compared with those in the circulation. Previously, it is believed that sFasL can bind to Fas but cannot activate its downstream signaling events. This activity, however, could be restored if two sFasL are physically linked at the contact site with the target cell.²² Consistently, it has been recently shown that sFasL is able to induce cardiomyocyte hypertrophy but not apoptosis through inactivation of glycogen synthase 3ß.¹³ In addition, we found that sFasL induces Akt activation in cultured ECs and that Fas engagement with the agonistic antibody Jo2 also induced Akt activation in aortic segments (Figure 2C), suggesting that Fas engagement with the membrane-bound form of FasL and sFasL can induce Akt activation in ECs.

Consistent with a possible role for Fas signaling to mediate eNOS expression in ECs in vivo, lpr mice, which express decreased cell surface Fas, had impairment of endothelium-dependent vascular relaxation and slightly higher systolic blood pressure compared with wild-type mice. In addition, chronic inhibition of NOS with L-NAME failed to exhibit further increases in blood pressure in lpr mice, whereas systolic blood pressure progressively increased in the L-NAME-treated wild-type mice, suggesting that diminished nitric oxide synthesis is partially responsible for the elevated blood pressure in lpr mice. Thus, Fas signaling might be important in the maintenance of endothelial function and the regulation of blood pressure in the cardiovascular system. Consistently, it has been shown that hypertension develops in eNOS-deficient mice.¹⁴ Suda et al,²³ however, recently reported that chronic inhibition of NOS by L-NAME induces perivascular fibrosis and upregulation of local angiotensin-converting enzyme expression in coronary microvessels with decreased blood pressure in eNOS-deficient mice, and suggested that chronic inhibition of NOS by L-NAME are not mediated by simple inhibition of eNOS. In this regard, it is notable that Fas receptor signaling is suggested to be a novel signal necessary for cardiac hypertrophy in response to the biomechanical stress of pressure overload and angiotensin II.¹³ In addition, it has been shown that chronic NOS inhibition induces cardiac hypertrophy via increased local angiotensin-converting enzyme expression,²⁴ suggesting that the failure of cardiac hypertrophy might also be involved in the mechanism underlying unresponsiveness of lpr mice to induce hypertension after L-NAME administration. However, it is possible that some unknown compensatory mechanisms could be additionally involved in these mechanisms. Thus, further studies are necessary to clarify the exact mechanism by which long-term NOS inhibition does not induce a further increase in the levels of blood pressure in lpr mice.

In conclusion, we demonstrated for the first time to our knowledge that Fas signaling may mediate upregulation of endothelial eNOS expression in the Akt signal-dependent manner and that loss of function of the Fas mutation may cause hypertension via impairment of endothelium-dependent nitric oxide generation.

Perspectives
Fas signaling regulates endothelium-derived nitric oxide generation in the survival signal Akt-dependent manner. Thus, Fas could be a new therapeutic target for nitric oxide-related pathological conditions such as hypertension, atherosclerosis, and angiogenesis.

	Acknowledgments

 
We thank Taeko Kaimoto for her excellent technical assistance. This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan.

Received November 20, 2003; first decision December 1, 2003; accepted January 12, 2004.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Nagata S. Apoptosis by death factor. Cell. 1997; 88: 355–365.[CrossRef][Medline] [Order article via Infotrieve]
2. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995; 270: 1189–1192.[Abstract/Free Full Text]
3. Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC. A role for CD95 ligand in preventing graft rejection. Nature. 1995; 377: 630–632.[CrossRef][Medline] [Order article via Infotrieve]
4. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyoshi K, Mizuki M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S. Fas ligand in human serum. Nat Med. 1996; 2: 317–322.[CrossRef][Medline] [Order article via Infotrieve]
5. Yamaguchi S, Yamaoka M, Okuyama M, Nitoube J, Fukui A, Shirakabe M, Shirakawa K, Nakamura N, Tomoike H. Elevated circulating levels and cardiac secretion of soluble Fas ligand in patients with congestive heart failure. Am J Cardiol. 1999; 83: 1500–1503.[CrossRef][Medline] [Order article via Infotrieve]
6. Shimizu M, Fukuo K, Nagata S, Suhara T, Okuro M, Fujii K, Higashino Y, Mogi M, Hatanaka Y, Ogihara T. Increased plasma levels of the soluble form of Fas ligand in patients with acute myocardial infarction and unstable angina pectoris. J Am Coll Cardiol. 2002; 39: 585–590.[Abstract/Free Full Text]
7. Sata M, Walsh K. TNFalpha regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nat Med. 1998; 4: 415–420.[CrossRef][Medline] [Order article via Infotrieve]
8. Mogi M, Fukuo K, Yang J, Suhara T, Ogihara T. Hypoxia stimulates release of the soluble form of fas ligand that inhibits endothelial cell apoptosis. Lab Invest. 2001; 81: 177–184.[Medline] [Order article via Infotrieve]
9. Yang J, Jones SP, Suhara T, Greer JJ, Ware PD, Nguyen NP, Perlman H, Nelson DP, Lefer DJ, Walsh K. Endothelial cell overexpression of fas ligand attenuates ischemia-reperfusion injury in the heart. J Biol Chem. 2003; 278: 15185–15191.[Abstract/Free Full Text]
10. Choy JC, Granville DJ, Hunt DW, McManus BM. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol. 2001; 33: 1673–1690.[CrossRef][Medline] [Order article via Infotrieve]
11. Sata M, Suhara T, Walsh K. Vascular endothelial cells and smooth muscle cells differ in expression of Fas and Fas ligand and in sensitivity to Fas ligand-induced cell death: implications for vascular disease and therapy. Arterioscler Thromb Vasc Biol. 2000; 20: 309–316.[Abstract/Free Full Text]
12. Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK. Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol. 2003; 5: 118–125.[CrossRef][Medline] [Order article via Infotrieve]
13. Badorff C, Ruetten H, Mueller S, Stahmer M, Gehring D, Jung F, Ihling C, Zeiher AM, Dimmeler S. Fas receptor signaling inhibits glycogen synthase kinase 3 beta and induces cardiac hypertrophy following pressure overload. J Clin Invest. 2002; 109: 373–381.[CrossRef][Medline] [Order article via Infotrieve]
14. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, Sherman PA, Sessa WC, Smithies O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1996; 93: 13176–13181.[Abstract/Free Full Text]
15. Kennedy NJ, Kataoka T, Tschopp J, Budd RC. Caspase activation is required for T cell proliferation. J Exp Med. 1999; 190: 1891–1896.[Abstract/Free Full Text]
16. Wollert KC, Heineke J, Westermann J, Ludde M, Fiedler B, Zierhut W, Laurent D, Bauer MK, Schulze-Osthoff K, Drexler H. The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system : relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Circulation. 2000; 101: 1172–1178.[Abstract/Free Full Text]
17. Panka DJ, Mano T, Suhara T, Walsh K, Mier JW. Phosphatidylinositol 3-kinase/Akt activity regulates c-FLIP expression in tumor cells. J Biol Chem. 2001; 276: 6893–6896.[Abstract/Free Full Text]
18. Suzuki T, Fukuo K, Suhara T, Yasuda O, Sato N, Takemura Y, Tsubakimoto M, Ogihara T. Eicosapentaenoic acid protects endothelial cells against anoikis through restoration of cFLIP. Hypertension. 2003; 42: 342–348.[Abstract/Free Full Text]
19. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999; 399: 597–601.[CrossRef][Medline] [Order article via Infotrieve]
20. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999; 399: 601–605.[CrossRef][Medline] [Order article via Infotrieve]
21. Abe R, shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H. Toxic epidermal necrosis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol. 2003; 162: 1515–1520.[Abstract/Free Full Text]
22. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, Tinel A, Deperthes D, Calderara S, Schulthess T, Engel J, Schneider P, Tschopp J. Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol. 2003; 23: 1428–1440.[Abstract/Free Full Text]
23. Suda O, Tsutsui M, Morishita T, Tanimoto A, Horiuchi M, Tasaki H, Huang PL, Sasaguri Y, Yanagihara N, Nakashima Y. Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice. Circulation. 2002; 106: 1729–1735.[Abstract/Free Full Text]
24. Takemoto M, Egashira K, Usui M, Numaguchi K, Tomita H, Tsutsui H, Shimokawa H, Sueishi K, Takeshita A. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest. 1997; 99: 278–287.[Medline] [Order article via Infotrieve]

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This Article Abstract Full Text (PDF) All Versions of this Article: 43/4/880    most recent 01.HYP.0000120124.27641.03v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takemura, Y. Articles by Ogihara, T. Search for Related Content PubMed PubMed Citation Articles by Takemura, Y. Articles by Ogihara, T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB PHENYLEPHRINE Related Collections Endothelium/vascular type/nitric oxide Apoptosis