Effects of Redox-Related Congeners of NO on Apoptosis and Caspase-3 Activity

Haendeler, Judith; Weiland, Ulrike; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1006/niox.1997.0134

Cited by 92 publications

(45 citation statements)

References 46 publications

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“…We had previously shown that NO increases the migratory capacity of EC 2 and decreases apoptosis rates. 12 In line with these findings, NO induced a nearly 3-fold increase in the level of the SOM1 transcript, whereas the amount of SOM3 mRNA was reduced to ≈70% compared with untreated cells after 18 hours ( Figure 2E). This reciprocal regulation clearly shows that physiological stimuli change the balance between these 2 isoforms of the transcription factor.…”

Section: Som1 and Som3 Have Opposing Effects On Endothelial Cell Migrsupporting

confidence: 83%

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Haendeler

Mlynek²,

Büchner³

et al. 2013

ATVB

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Objective— Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells. Approach and Results— Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect. Conclusions— Our data demonstrate that the splice variant–derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.

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Section: Som1 and Som3 Have Opposing Effects On Endothelial Cell Migrsupporting

confidence: 83%

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Haendeler

Mlynek²,

Büchner³

et al. 2013

ATVB

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“…One of these closely related conditions is the cellular redox status (46). Signaling pathways that regulate the redox status require cross-talk with NO signaling pathways to maintain cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

An NADPH Sensor Protein (HSCARG) Down-regulates Nitric Oxide Synthesis by Association with Argininosuccinate Synthetase and Is Essential for Epithelial Cell Viability

Zhao

Zhang

et al. 2008

Journal of Biological Chemistry

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NADPH is an important cofactor in many biosynthesis pathways that control fundamental cellular processes. We recently determined the crystal structure of HSCARG, with functions previously unknown, and demonstrated it is an NADPH sensor, which undergoes restructuring and redistribution in response to changes of intracellular NADPH/NADP levels. In this study, we identified argininosuccinate synthetase (AS), a rate-limiting enzyme in nitric oxide synthesis, as capable of associating with HSCARG and demonstrated further that HSCARG decreased nitric oxide synthesis by down-regulating AS activity, whereas AS overexpression up-regulated hscarg mRNA transcription, suggesting a negative feedback mechanism. A decrease in the NADPH/NADP ؉ ratio, induced by dehydroepiandrosterone treatment, enhanced the interaction between HSCARG and AS, which resulted in stronger inhibition of AS activity and nitric oxide production. The dimerization region of HSCARG, amino acids 153-189, was identified to undergo critical interactions with AS. Furthermore, the viability of HSCARG RNA interference-treated epithelial cells decreased significantly, accompanied by an increase of the activity of caspase-3, which suggested that the loss of viability was because of apoptosis. These results indicate that HSCARG regulation of AS activity is crucial for maintaining the intracellular balance between redox state and nitric oxide levels.Nitric oxide (NO), 2 a cellular signaling molecule, has been shown to be involved in vascular regulation, autoimmunity, and neurotransmission and impacts diverse biological processes, including cell survival (1-7). The impaired production of NO can result in the vascular dysfunction, whereas overproduction of NO will induce some diseases such as the cerebral infarction, diabetes mellitus, and neurodegenerative disorders (7-11). Arginine is the sole amino acid substrate that is required for the production of NO (12, 13), and its regeneration from citrulline, the co-product of NO synthesis, is rate-limited by argininosuccinate synthetase (AS) (13-16). In addition, the reducing reagent donor, NADPH, and oxygen are necessary for NO production (13, 17). For this reason, NO production is not only limited by the regeneration of arginine but is also affected by the intracellular NADPH concentration, which requires cross-talk between the signaling pathways of NADPH and NO.In addition to its well known function in energy metabolism, NADH, along with its phosphorylated relative NADPH, has been recognized as an important regulatory molecule. Together, their roles are crucial in signaling pathways that control fundamental cellular processes, such as transcription, regulation of calcium homeostasis, and apoptosis (18 -20). NAD mainly exists in its oxidized state (NAD ϩ ), whereas NADP is largely found in its reduced form, NADPH (21, 22). The predominant function of NADP is to maintain a pool in its reduced form to ensure a rapid regeneration of the defense systems to protect cells from oxidative damage. NADPH holds a key position in...

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“…58,59 Physiological determinants of this regulation may be additionally complicated by interactions between NO and glutathione in caspase regulation. 60,61 In a recent study, it was noted that HeLa cells overexpressing the antiapoptotic protein, Bcl-2, accumulate GSH within the nucleus. 62 Even though not directly addressed in that study, this finding raises the possibility that a modulation of apoptotic signaling by GSH compartmentalization may represent an additional regulatory action of Bcl-2, complementing the currently known pleiotropic functions of this protein.…”

Section: Discussionmentioning

confidence: 99%

CD95-mediated murine hepatic apoptosis requires an intact glutathione status

et al. 1999

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Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo, we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dosedependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N-acetyl cysteine, ␣-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione. (HEPATOLOGY 1999;30:177-185.)The cytokine receptor CD95 (synonyms: APO-1/Fas) belongs to the tumor necrosis factor (TNF)/nerve growth factor receptor superfamily. The death receptors in this family share the death domain, i.e., a conserved intracellular motive that transduces the apoptotic signal via activation of intracellular cysteine proteases, the caspases. 1 CD95 is expressed by lymphoid and nonlymphoid cells and is regarded as a principal trigger for apoptotic cell death of hepatocytes. 2,3 In human as well as murine liver, TNF-R1 and CD95 are independent triggers of apoptosis, and the application of the activating anti-CD95 antibody (␣CD95) in mice leads to lethal liver destruction within hours as a result of massive apoptosis of hepatocytes. 4,5 There is growing evidence for the involvement of CD95 in the physiological regulation of hepatocyte turnover, as well as in the pathophysiology of several liver diseases such as viral hepatitis, transplant rejection, and hepatitis caused by inflammatory stimuli. [6][7][8] Similar to cells of immune-privileged sites, tumor cells display an elevated expression of the CD95 ligand (CD95L) and a concomitant dysfunction of CD95, which, for instance, renders hepatocellular carcinomas resistant toward attac...

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Effects of Redox-Related Congeners of NO on Apoptosis and Caspase-3 Activity

Cited by 92 publications

References 46 publications

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

Two Isoforms of Sister-of-Mammalian Grainyhead Have Opposing Functions in Endothelial Cells and In Vivo

An NADPH Sensor Protein (HSCARG) Down-regulates Nitric Oxide Synthesis by Association with Argininosuccinate Synthetase and Is Essential for Epithelial Cell Viability

CD95-mediated murine hepatic apoptosis requires an intact glutathione status

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