Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Khan, MJ; Alam, MR; Waldeck-Weiermair, M; Karsten, F; Groschner, L; Riederer, M; Hallstroem, S; Rockenfeller, P; Konya, V; Heinemann, A; Madeo, F; Graier, WF; Malli, R.
Inhibition of autophagy rescues palmitic acid induced necroptosis of endothelial cells.
J Biol Chem. 2012; 287(25):21110-21120 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Alam Muhammad Rizwan
Graier Wolfgang
Groschner Lukas
Hallström Seth
Heinemann Akos
Karsten Felix Daniel
Khan Muhammad Jadoon
Konya Viktoria
Malli Roland
Riederer Monika
Waldeck-Weiermair Markus
Altmetrics:

Dimensions Citations:

Plum Analytics:
Number of Figures: 6
| | | | | |
Abstract:
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.
Find related publications in this database (using NLM MeSH Indexing)
Autophagy - drug effects
Calcium Signaling -
Cells, Cultured -
Chelating Agents - pharmacology
Class III Phosphatidylinositol 3-Kinases - genetics Class III Phosphatidylinositol 3-Kinases - metabolism
Egtazic Acid - analogs and derivatives
Endothelial Cells - metabolism Endothelial Cells - pathology
Enzyme Inhibitors - pharmacokinetics
Gene Expression Regulation, Enzymologic - drug effects
Gene Knockdown Techniques -
Humans -
Necrosis -
Palmitic Acid - pharmacology
RNA, Messenger - biosynthesis RNA, Messenger - genetics
Receptor-Interacting Protein Serine-Threonine Kinases - genetics Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
Tumor Suppressor Proteins -
Ubiquitin-Activating Enzymes - genetics Ubiquitin-Activating Enzymes - metabolism

© Meduni Graz Impressum