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SHR Neuro Krebs Kardio Lipid

Koyani, CN; Windischhofer, W; Rossmann, C; Jin, G; Kickmaier, S; Heinzel, FR; Groschner, K; Alavian-Ghavanini, A; Sattler, W; Malle, E.
15-deoxy-Δ¹²,¹⁴-PGJ₂ promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis.
Int J Cardiol. 2014; 173(3):472-480 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Autor/innen der Med Uni Graz:
Alavian Ghavanini Ali
Groschner Klaus
Heinzel Frank
Jin Ge
Koyani Chintan Navinchandra
Malle Ernst
Rossmann Christine Renate
Sattler Wolfgang
Windischhofer Werner

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Plum Analytics:
Number of Figures: 8
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Prostaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD₂ synthase is abundantly expressed in heart tissue and PGD₂ has recently been found to induce cardiomyocyte apoptosis. PGD₂ is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ¹²,¹⁴-PGJ₂ (15d-PGJ₂, present at high levels in ischemic myocardium) might cause cardiomyocyte damage. Using specific (ant)agonists we show that 15d-PGJ₂ induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ₂ enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ₂ (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling. We conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ₂ is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ₂-induced myocardial injury. Copyright © 2014. Published by Elsevier Ireland Ltd.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Apoptosis - drug effects
Apoptosis - physiology
Cells, Cultured -
Inflammation - metabolism
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Mice -
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Prostaglandin D2 - analogs & derivatives
Prostaglandin D2 - pharmacology
Receptors, Immunologic - agonists
Receptors, Immunologic - metabolism
Receptors, Prostaglandin - agonists
Receptors, Prostaglandin - metabolism
Tumor Necrosis Factor-alpha - metabolism

Find related publications in this database (Keywords)
TNF alpha
PGD(2) receptor
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