15-deoxy-Δ¹²,¹⁴-PGJ₂ promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Chintan N
CN
Koyani
Department of Pediatrics and Adolescence Medicine, Research Unit of Osteological Research and Analytical Mass Spectrometry, Medical University of Graz, Austria.
Werner
W
Windischhofer
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Christine
C
Rossmann
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria; Cardiology Department, Medical University of Wenzhou, Wenzhou, China.
Ge
G
Jin
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Sandra
S
Kickmaier
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria.
Frank R
FR
Heinzel
Institute of Biophysics, Medical University of Graz, Austria.
Klaus
K
Groschner
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Ali
A
Alavian-Ghavanini
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
Wolfgang
W
Sattler
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: ernst.malle@medunigraz.at.
Ernst
E
Malle
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000819:agonists / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
15d-PGJ(2); Apoptosis; Cardiomyocytes; PGD(2) receptor; TNFα