Requirement of nitric oxide and calcium mobilization for the induction of apoptosis in adrenal vascular endothelial cells

Vascular endothelial cells are the prime target in ischemia reperfusion injury. Growing evidence has shown that one of the main etiologies is considered to be reactive oxygen species (ROS) that induce endothelial‐cell death either by necrosis or apoptosis. Cultured porcine endothelial cells were transfected with human copper, zinc‐superoxide dismutase (h‐Cu, Zn‐SOD) to investigate whether these cells can prevent apoptosis from oxidative injury in vitro. The endothelial cells were cultured with SIN‐1 (3‐morpholinosydnonimine‐N‐ethylcarbanride) as a donor of peroxinitrite (ONOO−). The control cells without the gene transfection developed characteristic apoptotic changes both morphologically and biochemically when they were incubated with SIN‐1 of 200 M. However, the cells showed necrosis predominantly when the concentration of SIN‐1 was 1,000 M. On the other hand, the cells transfected with h‐Cu, Zn‐SOD showed significantly less evidence of apoptotic change after exposure to SIN‐1. Nitric oxide (NO) did not significantly affect the viability of either the control cells or the transfected cells. One of the potent ROS, peroxinitrite, is considered to play a significant role in sichemia reperfusion injury. SIN‐1 can produce peroxinitrite in vitro that induces endothelial‐cell damage by apoptosis. This type of cytotoxicity can be successfully prevented by transfection of the h‐Cu, Zn‐SOD into the cells.

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“…Rather, the value of SOD is to prevent the reaction of NO and 0; to form ONOO-. This finding is consistent with the reports of others [18].…”

Section: Discussionsupporting

confidence: 94%

Prevention of free-radical induced apoptosis by induction of human recombinant Cu, Zn-SOD in pig endothelial cells

et al. 2002

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“…Physiologically relevant concentrations of peroxynitrite have induced apoptosis in HL-60 and U-937 cells, but they appeared ineffective in inducing HUVEC apoptosis (50). A combination of NO and calcium mobilization has been shown to potentiate apoptosis in adrenal vascular endothelial cells (59). In the present study, NOS expression and NO production could be detected in HMEC-1 cells after binding with anti-NS1.…”

Section: Discussionmentioning

confidence: 42%

Endothelial Cell Apoptosis Induced by Antibodies Against Dengue Virus Nonstructural Protein 1 Via Production of Nitric Oxide

Lin

Lei

Shiau

et al. 2002

The Journal of Immunology

165

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The onset of vascular leakage and hemorrhagic diathesis is one of the life-threatening complications occurring in dengue patients, yet the pathogenic mechanisms are not well understood. In this study, we demonstrated that Abs against dengue virus nonstructural protein 1 (NS1) generated in mice cross-reacted with human endothelial cells and mouse vessel endothelium. After binding, mouse anti-NS1 Abs induced endothelial cell apoptosis in a caspase-dependent manner. Inducible NO synthase expression could be observed; it showed a time- and dose-dependent correlation with NO production. Endothelial cell apoptosis, characterized by exposure of phosphatidylserine on the cell surface and nuclear DNA fragmentation, was blocked by treatment with the NO synthase inhibitor Nω-nitro-l-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-xL decreased in both mRNA and protein levels, whereas p53 and Bax increased after anti-NS1 treatment. Cytochrome c release was also observed. All of these effects could be inhibited by Nω-nitro-l-arginine methyl ester. Taken together, anti-NS1 Abs act as autoantibodies that cross-react with noninfected endothelial cells and trigger the intracellular signaling leading to the production of NO and to apoptosis. Endothelial cell damage may cause vascular leakage that contributes to the pathogenesis of dengue disease.

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“…However, in several tissues and organs, including the ovary, the expression of iNOS is correlated with cytotoxic/cytostatic events and results in a sustained synthesis of NO, which in turn induces apoptotic cell death [35,46]. In fact, [Ca 2ϩ ] i -mobilizing agents and cytokines elicit an apoptotic response in the vascular endothelial cells through mechanisms that require NO synthesis [47]. We have also found that spermine NONOate (an NO donor) strongly reduces the viability of late luteal cells, whereas L-NAME (an NOS inhibitor) had opposite effects (Korzekwa, Okuda, Jaroszewski, Skarzynski, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Administration of a Nitric Oxide Synthase Inhibitor Counteracts Prostaglandin F2-Induced Luteolysis in Cattle1

Skarzynski

Jaroszewski

Bah

et al. 2003

Biology of Reproduction

109

155

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The objective of this study was to determine whether nitric oxide (NO) is produced locally in the bovine corpus luteum (CL) and whether NO mediates prostaglandin F2alpha (PGF2alpha)-induced regression of the bovine CL in vivo. The local production of NO was determined in early I, early II, mid, late, and regressed stages of CL by determining NADPH-d activity and the presence of inducible and endothelial NO synthase immunolabeling. To determine whether inhibition of NO production counteracts the PGF2alpha-induced regression of the CL, saline (10 ml/h; n = 10) or a nonselective NOS inhibitor (Nomega-nitro-l-arginine methyl ester dihydrochloride [L-NAME]; 400 mg/h; n = 9) was infused for 2 h on Day 15 of the estrous cycle into the aorta abdominalis of Holstein/Polish Black and White heifers. After 30 min of infusion, saline or cloprostenol, an analogue of PGF2alpha (aPGF2alpha; 100 microg) was injected into the aorta abdominalis of animals infused with saline or L-NAME. NADPH-diaphorase activity was present in bovine CL, with the highest activity at mid and late luteal stages (P < 0.05). Inducible and endothelial NO synthases were observed with the strongest immunolabeling in the late CL (P < 0.05). Injection of aPGF2alpha increased nitrite/nitrate concentrations (P < 0.01) and inhibited P4 secretion (P < 0.05) in heifers that were infused with saline. Infusion of L-NAME stimulated P4 secretion (P < 0.05) and concomitantly inhibited plasma concentrations of nitrite/nitrate (P < 0.05). Concentrations of P4 in heifers infused with L-NAME and injected with aPGF2alpha were higher (P < 0.05) than in animals injected only with aPGF2alpha. The PGF2alpha analogue shortened the cycle length compared with that of saline (17.5 +/- 0.22 days vs. 21.5 +/- 0.65 days P < 0.05). L-NAME blocked the luteolytic action of the aPGF2alpha (22.6 +/- 1.07 days vs. 17.5 +/- 0.22 days, P < 0.05). These results suggest that NO is produced in the bovine CL. NO inhibits luteal steroidogenesis and it may be one of the components of an autocrine/paracrine luteolytic cascade induced by PGF2alpha.

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Requirement of nitric oxide and calcium mobilization for the induction of apoptosis in adrenal vascular endothelial cells

Cited by 39 publications

References 24 publications

Prevention of free-radical induced apoptosis by induction of human recombinant Cu, Zn-SOD in pig endothelial cells

Prevention of free-radical induced apoptosis by induction of human recombinant Cu, Zn-SOD in pig endothelial cells

Endothelial Cell Apoptosis Induced by Antibodies Against Dengue Virus Nonstructural Protein 1 Via Production of Nitric Oxide

Administration of a Nitric Oxide Synthase Inhibitor Counteracts Prostaglandin F2-Induced Luteolysis in Cattle1

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