Expression of inducible nitric oxide synthase in T lymphocytes and macrophages of cholesterol-fed rabbits

Esaki, Teiji; Hayashi, Toshio; Muto, Etsuko; Yamada, Kazuyoshi; Kuzuya, Masafumi; Iguchi, Akihisa

doi:10.1016/s0021-9150(96)05976-x

Cited by 91 publications

(51 citation statements)

References 32 publications

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“…This paradigm is consistent with our coimmunoreactivity of macrophages in ruptured plaques for iNOS and Fas-L, which is reasonably consistent with studies on unruptured plaques. 35,36 Although VSMCs in plaques sit within matrix cages 37 that might be expected to impede cell-cell contact, activated macrophages within plaques are armed with proteases, such as metalloproteinases, that are important in plaque rupture 6 and could lyse the matrix around VSMCs, permitting cell-cell proximity.…”

Section: Discussionmentioning

confidence: 99%

Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions

Boyle

Weissberg

Bennett

2002

ATVB

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Objective-We have previously shown that macrophages induce vascular smooth muscle cell (VSMC) apoptosis in vitro by cell-cell proximity and Fas-L/Fas interactions. Because NO is a short-range mediator, we tested whether NO mediates macrophage-induced VSMC apoptosis. Methods and Results-NO synthase (NOS) inhibitors markedly inhibited macrophage-induced apoptosis of carotid plaqueVSMCs (apoptotic indices, 81Ϯ2.9% for control and 28.2Ϯ3.9% for N G -nitro-L-arginine methyl ester [L-NAME] treatment) and coronary medial VSMCs (apoptotic indices, 76Ϯ5.5% for control and 3.5Ϯ0.8% for L-NAME treatment). Inactive enantiomers were without effect (PϾ0.05). Cultured macrophages, but not VSMCs, expressed inducible NOS (but not neuronal NOS or endothelial NOS) concomitant with activation and secreted 1.51Ϯ0.3 fmol nitrite per cell, which was blocked by L-NAME (100 mol/L). Diethylene triamine nitric oxide (DETA/NO) and sodium nitroprusside (NO donors) induced VSMC cell-surface Fas and enhanced plaque VSMC apoptosis induced by agonistic anti-Fas antibody (apoptotic indices, 6.6Ϯ1.8% for control, 6.3Ϯ1.5% for DETA/NO, 26Ϯ1.8% for Fas, and 44Ϯ6.9% for FasϩDETA/NO). In isolated macrophages, NOS inhibitors reduced and NO donors increased surface Fas-L, indicating an NO-dependent autocrine enhancement of macrophage surface Fas-L. Conclusions-Together, these data indicate that macrophage-derived NO is required for macrophage-induced VSMC apoptosis and that it acts by enhancing Fas-L/Fas interactions. Key Words: macrophages Ⅲ plaque rupture Ⅲ vascular smooth muscle cells Ⅲ nitric oxide Ⅲ Fas T he rupture of human atherosclerotic plaques causes myocardial and cerebral infarction. 1 Atherosclerotic plaque rupture is associated with infiltration of the fibrous cap by macrophages and T lymphocytes and with reduced numbers of vascular smooth muscle cells (VSMCs). 1,2 An important mode of loss of plaque in VSMCs is through apoptosis, 3 which is increased in plaque compared with normal vessels and is higher in ruptured than in stable plaque. 4,5 Because VSMCs are the only cells within plaque that are capable of synthesizing structurally important collagen isoforms, VSMC apoptosis may therefore promote plaque rupture. 6 We have recently shown that human blood-derived macrophages induce human VSMC apoptosis in coculture via cell-cell proximity and Fas-L/Fas signaling. 7 Macrophage-derived NO is cytotoxic to tumor cells 8,9 by an uncertain mechanism and has a short half-life and path length in physiological solution. 10 Therefore, we wondered whether NO contributes to proximity-dependent macrophage-induced VSMC apoptosis.Macrophages synthesize the unstable free radical NO. 11 There are 3 isoenzymes of NO synthase (NOS): NOS I, NOS II, and NOS III. 11 NOS I (endothelial NOS [eNOS]) is expressed by endothelial cells, and NOS III (neuronal NOS [nNOS]) is expressed by neurons. 11 NOS I and NOS III are low-output pathways. 11 The inducible NOS (iNOS) pathway is a high-output pathway that may liberate NO in a sufficient concentration to damage by dire...

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Section: Discussionmentioning

confidence: 99%

Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions

Boyle

Weissberg

Bennett

2002

ATVB

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“…8 DHEA was also reported to antagonize the suppressive effects of dexamethasone on T-and B-lymphocyte proliferation in mice. 59 T lymphocytes are known to be present and to play a certain role in atherosclerosis 60 ; however, that role has not been fully established. Although the population and distribution of T cells in an atherosclerotic lesion after DHEA treatment did not show any change in our preliminary observations, the possibility of an antiatherosclerotic effect of DHEA through the receptor-mediated system of activating T lymphocytes remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Hayashi

Esaki

Muto

et al. 2000

ATVB

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Abstract-Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), a specific aromatase inhibitor; group 4, an HCD plus 17␤-estradiol (20 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by Ϸ60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that Ϸ50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17␤-estradiol. have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEA-S serves as a reservoir for DHEA, since various tissues have been shown to contain steroid sulfatases. 1 The peak plasma levels of DHEA and DHEA-S occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95% around the age of 85 years. Epidemiological evidence has shown that adult men with high plasma DHEA-S levels are less likely to die of cardiovascular disease. 2 A study indicated that administration of DHEA reduced aortic fatty streak formation and cholesterol accumulation by Ϸ30% to 40% in cholesterol-fed rabbits. 3 Another report has shown a 50% reduction...

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“…Cell nuclei were counterstained with methyl green. 21 Negative controls included substitution of the primary antiserum with either PBS or irrelevant antibodies. Each field on the slide was scored for the number of macrophage antibody-positive cells and analyzed statistically as described in a previous report.…”

Section: Immunocytochemical Analysismentioning

confidence: 99%

“…Each field on the slide was scored for the number of macrophage antibody-positive cells and analyzed statistically as described in a previous report. 21 Five samples were prepared from each rabbit.…”

Section: Immunocytochemical Analysismentioning

confidence: 99%

Physiological Concentration of 17β-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury

Hayashi

Jayachandran

Sumi

et al. 2000

ATVB

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Abstract-The molecular mechanisms of the antiatherosclerotic effects of estrogen are not yet known. We evaluated the effects of 17␤-estradiol (E 2 ) on high cholesterol diet-(HCD; standard diet and 1% cholesterol) and balloon injury-induced atherosclerosis in female New Zealand White rabbits. The abdominal aortas of 40 oophorectomized (Groups 1 through 5) and 8 nonoophorectomized (Group 6) rabbits were injured by balloon catheter, and the animals were then divided into the following groups and treated for 10 weeks: Group 1, standard diet; Group 2, standard diet plus a moderate dose of E 2 (100 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); Group 3, HCD; Group 4, HCD plus a moderate dose of E 2 ; Group 5, HCD plus a low dose of E 2 (20 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); and Group 6, HCD in nonoophorectomized rabbits. After the treatment phase, plasma E 2 was increased up to 282.2Ϯ45.5 pg/mL in Group 2, 263.0Ϯ41.5 pg/mL in Group 4, 87.9Ϯ18.8 pg/mL in Group 5, and 45.6Ϯ7.3 pg/mL in Group 6. HCD-mediated increases in plasma lipid levels were not changed by E 2 treatment, whereas E 2 decreased the aortic intimal thickening in Group 2 animals compared with those in Group 1 and reduced atherosclerosis in the thoracic and abdominal aortas of Group 4, 5, and 6 rabbits compared with those in Group 3. E 2 restored the impaired abdominal aortic endothelium-dependent relaxation of balloon-injured and HCDsupplemented rabbits, and E 2 increased basal nitric oxide (NO) release. The basal NO-releasing effect showed a significant, inverse relation with the severity of atherosclerosis. Plasma E 2 concentration also showed a significant, inverse relation with atherosclerotic area. In conclusion, physiological concentrations of E 2 can retard the progression of severe atherosclerosis and stabilize atheromas induced by HCD and balloon injury. Key Words: nitric oxide Ⅲ estradiol Ⅲ arteriosclerosis Ⅲ balloon injury Ⅲ endothelium I t is well known that estrogen retards the development of atherosclerosis, 1 but the mechanisms of action are not clearly established. Estrogen replacement therapy suppresses the incidence of cardiovascular disease in postmenopausal women, 2 and it reduces plasma LDL cholesterol and increases HDL cholesterol levels. 3 However, the alterations in lipid profiles reportedly account for only a limited portion of the protective effects of estrogen against cardiovascular disease. 4 Estrogen exerts a direct action on the vessel wall via incompletely understood mechanisms. 5 Recently, estradiol was found to inhibit leukocyte adhesion and transendothelial migration in rabbits, which suggests one of the mechanisms of a direct antiatherosclerotic effect by estrogen on the vessel wall. 6 Nitric oxide (NO), released from endothelial nitric oxide synthase (endothelial NOS), has been demonstrated to offer protection against the development of atherosclerosis by producing vascular dilatation, inhibiting monocyte adhesion to the endothelium, and other modes of action. [7][8][9] We have found that estrogen acts via an NO-mediated system in vivo and in vitro. The aortas...

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Expression of inducible nitric oxide synthase in T lymphocytes and macrophages of cholesterol-fed rabbits

Cited by 91 publications

References 32 publications

Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions

Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Physiological Concentration of 17β-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury

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