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Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis.

Seko Y, Fujimura T, Yao T, Taka H, Mineki R, Okumura K, Murayama K - Sci Rep (2015)

Bottom Line: It causes cell damage that leads to apoptosis via uncertain mechanisms.Myocardial ischemia/reperfusion (but not ischemia alone) markedly increased the plasma levels of eIF5A, and treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial injury.These results identify an important, novel specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi-Bakurocho, Chuo-ku, Tokyo 103-0002, Japan.

ABSTRACT
Oxidative stress plays a critical role in ischemia/reperfusion-injury, atherosclerosis, and aging. It causes cell damage that leads to apoptosis via uncertain mechanisms. Because conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation induces extensive apoptosis of cardiac myocytes under normoxia, we hypothesized that a humoral factor released from the hypoxic/reoxygenated cardiac myocytes mediates apoptosis. We identified an apoptosis-inducing humoral factor in the hypoxia/reoxygenation-conditioned medium. Here, we found that eIF5A undergoes tyrosine sulfation in the trans-Golgi and is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation; then, eIF5A induces apoptosis by acting as a pro-apoptotic ligand. The apoptosis of cardiac myocytes induced by hypoxia/reoxygenation or ultraviolet irradiation was suppressed by anti-eIF5A neutralizing monoclonal antibodies (mAbs) in vitro. Myocardial ischemia/reperfusion (but not ischemia alone) markedly increased the plasma levels of eIF5A, and treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial injury. These results identify an important, novel specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury.

No MeSH data available.


Related in: MedlinePlus

Myocardial ischemia/reperfusion induces the release of eIF5A into the circulation, and the neutralization of eIF5A suppresses myocardial ischemia/reperfusion injury in vivo.(a) The plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion in vivo. P values were calculated using a paired t-test (n = 10). (b) Pretreatment with GC7 (Biosearch Technologies, Inc., 1 mg/kg intraperitoneally, daily from 5 days before until 1 day before ischemia/reperfusion) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart stained with triphenyl tetrazolium chloride (TTC) from the control group (upper panel) and the GC7-treated group (lower panel). (c) The infarct size of the GC7-treated rats was significantly smaller than that of the control PBS-treated rats (n = 12, *P = 0.001) (Mann-Whitney U-test; P values corrected using the Bonferroni method). (d) The anti-eIF5A neutralizing mAbs (YSP5-45-36 and YSPN2-74-18) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart from the mouse IgG-treated group (upper panel), the anti-eIF5A mAb (YSP5-45-36)-treated group (middle panel), and the anti-eIF5A mAb (YSPN2-74-18)-treated group (lower panel). (e) The infarct size in the anti-eIF5A mAb (YSP5-45-36 and YSPN2-74-18)-treated groups was significantly smaller than that in the mouse IgG-treated group (n = 12, *P < 0.0001 for both) (Dunnett's multiple comparison test).
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f5: Myocardial ischemia/reperfusion induces the release of eIF5A into the circulation, and the neutralization of eIF5A suppresses myocardial ischemia/reperfusion injury in vivo.(a) The plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion in vivo. P values were calculated using a paired t-test (n = 10). (b) Pretreatment with GC7 (Biosearch Technologies, Inc., 1 mg/kg intraperitoneally, daily from 5 days before until 1 day before ischemia/reperfusion) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart stained with triphenyl tetrazolium chloride (TTC) from the control group (upper panel) and the GC7-treated group (lower panel). (c) The infarct size of the GC7-treated rats was significantly smaller than that of the control PBS-treated rats (n = 12, *P = 0.001) (Mann-Whitney U-test; P values corrected using the Bonferroni method). (d) The anti-eIF5A neutralizing mAbs (YSP5-45-36 and YSPN2-74-18) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart from the mouse IgG-treated group (upper panel), the anti-eIF5A mAb (YSP5-45-36)-treated group (middle panel), and the anti-eIF5A mAb (YSPN2-74-18)-treated group (lower panel). (e) The infarct size in the anti-eIF5A mAb (YSP5-45-36 and YSPN2-74-18)-treated groups was significantly smaller than that in the mouse IgG-treated group (n = 12, *P < 0.0001 for both) (Dunnett's multiple comparison test).

Mentions: We developed a sandwich enzyme-linked immunosorbent assay (ELISA) using YSPN2-74-18 and YSP5-45-36 (Supplementary Fig. 16) and measured the plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion. No significant changes in the plasma eIF5A levels were observed between the control condition (before ischemia) and after 30 min of ischemia (immediately before reperfusion). However, these levels began to increase after reperfusion and were significantly increased 10–15 min after reperfusion (262.1 ± 39.0 ng/ml [mean ± s.e.m.]) compared with immediately before reperfusion (38.6 ± 11.8 ng/ml; n = 10, P = 0.0001) (Fig. 5a). The plasma levels of eIF5A were significantly increased in rats whose hearts were subjected to UV irradiation in vivo (Supplementary Fig. 17).


Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis.

Seko Y, Fujimura T, Yao T, Taka H, Mineki R, Okumura K, Murayama K - Sci Rep (2015)

Myocardial ischemia/reperfusion induces the release of eIF5A into the circulation, and the neutralization of eIF5A suppresses myocardial ischemia/reperfusion injury in vivo.(a) The plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion in vivo. P values were calculated using a paired t-test (n = 10). (b) Pretreatment with GC7 (Biosearch Technologies, Inc., 1 mg/kg intraperitoneally, daily from 5 days before until 1 day before ischemia/reperfusion) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart stained with triphenyl tetrazolium chloride (TTC) from the control group (upper panel) and the GC7-treated group (lower panel). (c) The infarct size of the GC7-treated rats was significantly smaller than that of the control PBS-treated rats (n = 12, *P = 0.001) (Mann-Whitney U-test; P values corrected using the Bonferroni method). (d) The anti-eIF5A neutralizing mAbs (YSP5-45-36 and YSPN2-74-18) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart from the mouse IgG-treated group (upper panel), the anti-eIF5A mAb (YSP5-45-36)-treated group (middle panel), and the anti-eIF5A mAb (YSPN2-74-18)-treated group (lower panel). (e) The infarct size in the anti-eIF5A mAb (YSP5-45-36 and YSPN2-74-18)-treated groups was significantly smaller than that in the mouse IgG-treated group (n = 12, *P < 0.0001 for both) (Dunnett's multiple comparison test).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4562266&req=5

f5: Myocardial ischemia/reperfusion induces the release of eIF5A into the circulation, and the neutralization of eIF5A suppresses myocardial ischemia/reperfusion injury in vivo.(a) The plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion in vivo. P values were calculated using a paired t-test (n = 10). (b) Pretreatment with GC7 (Biosearch Technologies, Inc., 1 mg/kg intraperitoneally, daily from 5 days before until 1 day before ischemia/reperfusion) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart stained with triphenyl tetrazolium chloride (TTC) from the control group (upper panel) and the GC7-treated group (lower panel). (c) The infarct size of the GC7-treated rats was significantly smaller than that of the control PBS-treated rats (n = 12, *P = 0.001) (Mann-Whitney U-test; P values corrected using the Bonferroni method). (d) The anti-eIF5A neutralizing mAbs (YSP5-45-36 and YSPN2-74-18) reduced myocardial ischemia/reperfusion injury. Representative cross-sections of a heart from the mouse IgG-treated group (upper panel), the anti-eIF5A mAb (YSP5-45-36)-treated group (middle panel), and the anti-eIF5A mAb (YSPN2-74-18)-treated group (lower panel). (e) The infarct size in the anti-eIF5A mAb (YSP5-45-36 and YSPN2-74-18)-treated groups was significantly smaller than that in the mouse IgG-treated group (n = 12, *P < 0.0001 for both) (Dunnett's multiple comparison test).
Mentions: We developed a sandwich enzyme-linked immunosorbent assay (ELISA) using YSPN2-74-18 and YSP5-45-36 (Supplementary Fig. 16) and measured the plasma levels of eIF5A in rats that were subjected to myocardial ischemia/reperfusion. No significant changes in the plasma eIF5A levels were observed between the control condition (before ischemia) and after 30 min of ischemia (immediately before reperfusion). However, these levels began to increase after reperfusion and were significantly increased 10–15 min after reperfusion (262.1 ± 39.0 ng/ml [mean ± s.e.m.]) compared with immediately before reperfusion (38.6 ± 11.8 ng/ml; n = 10, P = 0.0001) (Fig. 5a). The plasma levels of eIF5A were significantly increased in rats whose hearts were subjected to UV irradiation in vivo (Supplementary Fig. 17).

Bottom Line: It causes cell damage that leads to apoptosis via uncertain mechanisms.Myocardial ischemia/reperfusion (but not ischemia alone) markedly increased the plasma levels of eIF5A, and treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial injury.These results identify an important, novel specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi-Bakurocho, Chuo-ku, Tokyo 103-0002, Japan.

ABSTRACT
Oxidative stress plays a critical role in ischemia/reperfusion-injury, atherosclerosis, and aging. It causes cell damage that leads to apoptosis via uncertain mechanisms. Because conditioned medium from cardiac myocytes subjected to hypoxia/reoxygenation induces extensive apoptosis of cardiac myocytes under normoxia, we hypothesized that a humoral factor released from the hypoxic/reoxygenated cardiac myocytes mediates apoptosis. We identified an apoptosis-inducing humoral factor in the hypoxia/reoxygenation-conditioned medium. Here, we found that eIF5A undergoes tyrosine sulfation in the trans-Golgi and is rapidly secreted from cardiac myocytes in response to hypoxia/reoxygenation; then, eIF5A induces apoptosis by acting as a pro-apoptotic ligand. The apoptosis of cardiac myocytes induced by hypoxia/reoxygenation or ultraviolet irradiation was suppressed by anti-eIF5A neutralizing monoclonal antibodies (mAbs) in vitro. Myocardial ischemia/reperfusion (but not ischemia alone) markedly increased the plasma levels of eIF5A, and treatment with anti-eIF5A neutralizing mAbs significantly reduced myocardial injury. These results identify an important, novel specific biomarker and a critical therapeutic target for oxidative stress-induced cell injury.

No MeSH data available.


Related in: MedlinePlus