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BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha.

Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH - J. Exp. Med. (2003)

Bottom Line: Noxa is a candidate molecule mediating p53-induced apoptosis.We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha.Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-Koo, Seoul 130-701, Korea.

ABSTRACT
Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes, which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Using polymerase chain reaction-based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1alpha and mediates hypoxic cell death.

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Related in: MedlinePlus

Protection of brain from ischemia by suppression of Noxa expression. SE or AS oligonucleotides (2 μg in 1 μl) were injected into the lateral ventricle 4 h before MCA occlusion for 2 h. Brain was reperfused for 14 h, removed, and then cut into eight coronal slices. (A) Representative section stained with triphenyl tetrazolium chloride (TTC). (B) Western blot analysis of Noxa from the corresponding slices of rat brain. (C) Infarction volume was calculated after measuring the infarct areas on coronal brain sections as described in Materials and Methods. The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (*, P < 0.05).
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fig9: Protection of brain from ischemia by suppression of Noxa expression. SE or AS oligonucleotides (2 μg in 1 μl) were injected into the lateral ventricle 4 h before MCA occlusion for 2 h. Brain was reperfused for 14 h, removed, and then cut into eight coronal slices. (A) Representative section stained with triphenyl tetrazolium chloride (TTC). (B) Western blot analysis of Noxa from the corresponding slices of rat brain. (C) Infarction volume was calculated after measuring the infarct areas on coronal brain sections as described in Materials and Methods. The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (*, P < 0.05).

Mentions: To determine whether suppression of Noxa expression may affect the extent of cerebral ischemia in vivo, AS in cationic liposomes was administered into the right lateral ventricle of rats 4 h before MCAO. The rats were killed after 16 h of MCA occlusion and their brains were removed for evaluation of infarction volume. There was a significant decrease in infarct volume in rats given the Noxa AS compared with SE (Fig. 9, A and C) . Attenuations of Noxa expressions according to slice levels were observed in Western blot analysis (Fig. 9 B). The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (Fig. 9 C, *, P < 0.05).


BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha.

Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH - J. Exp. Med. (2003)

Protection of brain from ischemia by suppression of Noxa expression. SE or AS oligonucleotides (2 μg in 1 μl) were injected into the lateral ventricle 4 h before MCA occlusion for 2 h. Brain was reperfused for 14 h, removed, and then cut into eight coronal slices. (A) Representative section stained with triphenyl tetrazolium chloride (TTC). (B) Western blot analysis of Noxa from the corresponding slices of rat brain. (C) Infarction volume was calculated after measuring the infarct areas on coronal brain sections as described in Materials and Methods. The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (*, P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887730&req=5

fig9: Protection of brain from ischemia by suppression of Noxa expression. SE or AS oligonucleotides (2 μg in 1 μl) were injected into the lateral ventricle 4 h before MCA occlusion for 2 h. Brain was reperfused for 14 h, removed, and then cut into eight coronal slices. (A) Representative section stained with triphenyl tetrazolium chloride (TTC). (B) Western blot analysis of Noxa from the corresponding slices of rat brain. (C) Infarction volume was calculated after measuring the infarct areas on coronal brain sections as described in Materials and Methods. The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (*, P < 0.05).
Mentions: To determine whether suppression of Noxa expression may affect the extent of cerebral ischemia in vivo, AS in cationic liposomes was administered into the right lateral ventricle of rats 4 h before MCAO. The rats were killed after 16 h of MCA occlusion and their brains were removed for evaluation of infarction volume. There was a significant decrease in infarct volume in rats given the Noxa AS compared with SE (Fig. 9, A and C) . Attenuations of Noxa expressions according to slice levels were observed in Western blot analysis (Fig. 9 B). The infarction volume of the control animal (SE) was 154.24 ± 28.38 mm3, whereas that of the experimental group (AS) was reduced to 48.86 ± 13.46 mm3 (Fig. 9 C, *, P < 0.05).

Bottom Line: Noxa is a candidate molecule mediating p53-induced apoptosis.We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha.Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-Koo, Seoul 130-701, Korea.

ABSTRACT
Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes, which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Using polymerase chain reaction-based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1alpha and mediates hypoxic cell death.

Show MeSH
Related in: MedlinePlus