15-deoxy-Delta(12,14)- PGJ(2) promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNF alpha axis

作者：Koyani Chintan N; Windischhofer Werner; Rossmann Christine; Jin Ge; Kickmaier Sandra; Heinzel Frank R; Groschner Klaus; Alavian Ghavanini Ali; Sattler Wolfgang; Malle Ernst^*

来源：International Journal of Cardiology, 2014, 173(3): 472-480.

DOI：10.1016/j.ijcard.2014.03.086

• Cardiomyocytes
• TNF alpha
• 15d-PGJ(2)
• Apoptosis
• PGD(2) receptor

Background: Prostaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD(2) 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-Delta(12,14)-PGJ(2) (15d-PGJ(2), present at high levels in ischemic myocardium) might cause cardiomyocyte damage. %26lt;br%26gt;Methods and 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 PPAR.) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ2 enhanced transcription and translation of TNF alpha and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNF alpha significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and gamma H2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-kappa B and its downstream target p53. Of note, 9,10-dihydro- 15d-PGJ2 (lacking the electrophilic carbon atomin 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/TNFa signaling. %26lt;br%26gt;Conclusions: We conclude that the reactive a, alpha,beta unsaturated carbonyl group of 15d-PGJ2 is responsible for the pronounced upregulation of TNF alpha promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ(2)-induced myocardial injury.

• 出版日期2014-5-15
• 单位温州大学