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Article: Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia

TitleLipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia
Authors
Issue Date2017
Citation
Journal of Cellular Physiology, 2017, v. 232, n. 8, p. 2125-2134 How to Cite?
Abstract© 2016 Wiley Periodicals, Inc. Lipocalin-2 (Lcn2; also termed neutrophil gelatinase-associated lipocalin (NGAL)) levels correlate positively with heart failure (HF) yet mechanisms via which Lcn2 contributes to the pathogenesis of HF remain unclear. In this study, we used coronary artery ligation surgery to induce ischemia in wild-type (wt) mice and this induced a significant increase in myocardial Lcn2. We then compared wt and Lcn2 knockout (KO) mice and observed that wt mice showed greater ischemia-induced caspase-3 activation and DNA damage measured by TUNEL than Lcn2KO mice. Analysis of autophagy by LC3 and p62 Western blotting, LC3 immunohistochemistry and transmission electron microscopy (TEM) indicated that Lcn2 KO mice had a greater ischemia-induced increase in autophagy. Lcn2KO were protected against ischemia-induced cardiac functional abnormalities measured by echocardiography. Upon treating a cardiomyocyte cell line (h9c2) with Lcn2 and examining AMPK and ULK1 phosphorylation, LC3 and p62 by Western blot as well as tandem fluorescent RFP/GFP-LC3 puncta by immunofluorescence, MagicRed assay for lysosomal cathepsin activity and TEM we demonstrated that Lcn2 suppressed autophagic flux. Lcn2 also exacerbated hypoxia-induced cytochromc c release from mitochondria and caspase-3 activation. We generated an autophagy-deficient H9c2 cell model by overexpressing dominant-negative Atg5 and found significantly increased apoptosis after Lcn2 treatment. In summary, our data indicate that Lcn2 can suppress the beneficial cardiac autophagic response to ischemia and that this contributes to enhanced ischemia-induced cell death and cardiac dysfunction. J. Cell. Physiol. 232: 2125–2134, 2017. © 2016 Wiley Periodicals, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/293011
ISSN
2023 Impact Factor: 4.5
2023 SCImago Journal Rankings: 1.321
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSung, Hye Kyoung-
dc.contributor.authorChan, Yee Kwan-
dc.contributor.authorHan, Meng-
dc.contributor.authorJahng, James Won Suk-
dc.contributor.authorSong, Erfei-
dc.contributor.authorDanielson, Eric-
dc.contributor.authorBerger, Thorsten-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorSweeney, Gary-
dc.date.accessioned2020-11-17T14:57:41Z-
dc.date.available2020-11-17T14:57:41Z-
dc.date.issued2017-
dc.identifier.citationJournal of Cellular Physiology, 2017, v. 232, n. 8, p. 2125-2134-
dc.identifier.issn0021-9541-
dc.identifier.urihttp://hdl.handle.net/10722/293011-
dc.description.abstract© 2016 Wiley Periodicals, Inc. Lipocalin-2 (Lcn2; also termed neutrophil gelatinase-associated lipocalin (NGAL)) levels correlate positively with heart failure (HF) yet mechanisms via which Lcn2 contributes to the pathogenesis of HF remain unclear. In this study, we used coronary artery ligation surgery to induce ischemia in wild-type (wt) mice and this induced a significant increase in myocardial Lcn2. We then compared wt and Lcn2 knockout (KO) mice and observed that wt mice showed greater ischemia-induced caspase-3 activation and DNA damage measured by TUNEL than Lcn2KO mice. Analysis of autophagy by LC3 and p62 Western blotting, LC3 immunohistochemistry and transmission electron microscopy (TEM) indicated that Lcn2 KO mice had a greater ischemia-induced increase in autophagy. Lcn2KO were protected against ischemia-induced cardiac functional abnormalities measured by echocardiography. Upon treating a cardiomyocyte cell line (h9c2) with Lcn2 and examining AMPK and ULK1 phosphorylation, LC3 and p62 by Western blot as well as tandem fluorescent RFP/GFP-LC3 puncta by immunofluorescence, MagicRed assay for lysosomal cathepsin activity and TEM we demonstrated that Lcn2 suppressed autophagic flux. Lcn2 also exacerbated hypoxia-induced cytochromc c release from mitochondria and caspase-3 activation. We generated an autophagy-deficient H9c2 cell model by overexpressing dominant-negative Atg5 and found significantly increased apoptosis after Lcn2 treatment. In summary, our data indicate that Lcn2 can suppress the beneficial cardiac autophagic response to ischemia and that this contributes to enhanced ischemia-induced cell death and cardiac dysfunction. J. Cell. Physiol. 232: 2125–2134, 2017. © 2016 Wiley Periodicals, Inc.-
dc.languageeng-
dc.relation.ispartofJournal of Cellular Physiology-
dc.titleLipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/jcp.25672-
dc.identifier.pmid27800610-
dc.identifier.scopuseid_2-s2.0-85016428728-
dc.identifier.volume232-
dc.identifier.issue8-
dc.identifier.spage2125-
dc.identifier.epage2134-
dc.identifier.eissn1097-4652-
dc.identifier.isiWOS:000399973200020-
dc.identifier.issnl0021-9541-

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