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Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells
Accumulation of palmitic acid (PA) in cells from nonadipose tissues is known to induce lipotoxicity resulting in cellular dysfunction and death. The exact molecular pathways of PA-induced cell death are still mysterious. Here, we show that PA triggers autophagy, which did not counteract but in contr...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375534/ https://www.ncbi.nlm.nih.gov/pubmed/22556413 http://dx.doi.org/10.1074/jbc.M111.319129 |
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author | Khan, Muhammad Jadoon Rizwan Alam, Muhammad Waldeck-Weiermair, Markus Karsten, Felix Groschner, Lukas Riederer, Monika Hallström, Seth Rockenfeller, Patrick Konya, Viktoria Heinemann, Akos Madeo, Frank Graier, Wolfgang F. Malli, Roland |
author_facet | Khan, Muhammad Jadoon Rizwan Alam, Muhammad Waldeck-Weiermair, Markus Karsten, Felix Groschner, Lukas Riederer, Monika Hallström, Seth Rockenfeller, Patrick Konya, Viktoria Heinemann, Akos Madeo, Frank Graier, Wolfgang F. Malli, Roland |
author_sort | Khan, Muhammad Jadoon |
collection | PubMed |
description | Accumulation of palmitic acid (PA) in cells from nonadipose tissues is known to induce lipotoxicity resulting in cellular dysfunction and death. The exact molecular pathways of PA-induced cell death are still mysterious. Here, we show that PA triggers autophagy, which did not counteract but in contrast promoted endothelial cell death. The PA-induced cell death was predominantly necrotic as indicated by annexin V and propidium iodide (PI) staining, absence of caspase activity, low levels of DNA hypoploidy, and an early ATP depletion. In addition PA induced a strong elevation of mRNA levels of ubiquitin carboxyl-terminal hydrolase (CYLD), a known mediator of necroptosis. Moreover, siRNA-mediated knockdown of CYLD significantly antagonized PA-induced necrosis of endothelial cells. In contrast, inhibition and knockdown of receptor interacting protein kinase 1 (RIPK1) had no effect on PA-induced necrosis, indicating the induction of a CYLD-dependent but RIPK1-independent cell death pathway. PA was recognized as a strong and early inducer of autophagy. The inhibition of autophagy by both pharmacological inhibitors and genetic knockdown of the autophagy-specific genes, vacuolar protein sorting 34 (VPS34), and autophagy-related protein 7 (ATG7), could rescue the PA-induced death of endothelial cells. Moreover, the initiation of autophagy and cell death by PA was reduced in endothelial cells loaded with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-(acetoxymethyl) ester (BAPTA-AM), indicating that Ca(2+) triggers the fatal signaling of PA. In summary, we introduce an unexpected mechanism of lipotoxicity in endothelial cells and provide several novel strategies to counteract the lipotoxic signaling of PA. |
format | Online Article Text |
id | pubmed-3375534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-33755342012-06-19 Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells Khan, Muhammad Jadoon Rizwan Alam, Muhammad Waldeck-Weiermair, Markus Karsten, Felix Groschner, Lukas Riederer, Monika Hallström, Seth Rockenfeller, Patrick Konya, Viktoria Heinemann, Akos Madeo, Frank Graier, Wolfgang F. Malli, Roland J Biol Chem Cell Biology Accumulation of palmitic acid (PA) in cells from nonadipose tissues is known to induce lipotoxicity resulting in cellular dysfunction and death. The exact molecular pathways of PA-induced cell death are still mysterious. Here, we show that PA triggers autophagy, which did not counteract but in contrast promoted endothelial cell death. The PA-induced cell death was predominantly necrotic as indicated by annexin V and propidium iodide (PI) staining, absence of caspase activity, low levels of DNA hypoploidy, and an early ATP depletion. In addition PA induced a strong elevation of mRNA levels of ubiquitin carboxyl-terminal hydrolase (CYLD), a known mediator of necroptosis. Moreover, siRNA-mediated knockdown of CYLD significantly antagonized PA-induced necrosis of endothelial cells. In contrast, inhibition and knockdown of receptor interacting protein kinase 1 (RIPK1) had no effect on PA-induced necrosis, indicating the induction of a CYLD-dependent but RIPK1-independent cell death pathway. PA was recognized as a strong and early inducer of autophagy. The inhibition of autophagy by both pharmacological inhibitors and genetic knockdown of the autophagy-specific genes, vacuolar protein sorting 34 (VPS34), and autophagy-related protein 7 (ATG7), could rescue the PA-induced death of endothelial cells. Moreover, the initiation of autophagy and cell death by PA was reduced in endothelial cells loaded with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-(acetoxymethyl) ester (BAPTA-AM), indicating that Ca(2+) triggers the fatal signaling of PA. In summary, we introduce an unexpected mechanism of lipotoxicity in endothelial cells and provide several novel strategies to counteract the lipotoxic signaling of PA. American Society for Biochemistry and Molecular Biology 2012-06-15 2012-05-03 /pmc/articles/PMC3375534/ /pubmed/22556413 http://dx.doi.org/10.1074/jbc.M111.319129 Text en © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Cell Biology Khan, Muhammad Jadoon Rizwan Alam, Muhammad Waldeck-Weiermair, Markus Karsten, Felix Groschner, Lukas Riederer, Monika Hallström, Seth Rockenfeller, Patrick Konya, Viktoria Heinemann, Akos Madeo, Frank Graier, Wolfgang F. Malli, Roland Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title | Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title_full | Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title_fullStr | Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title_full_unstemmed | Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title_short | Inhibition of Autophagy Rescues Palmitic Acid-induced Necroptosis of Endothelial Cells |
title_sort | inhibition of autophagy rescues palmitic acid-induced necroptosis of endothelial cells |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375534/ https://www.ncbi.nlm.nih.gov/pubmed/22556413 http://dx.doi.org/10.1074/jbc.M111.319129 |
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