Anandamide and decidual remodelling: COX-2 oxidative metabolism as a key regulator.
Recently, endocannabinoids have emerged as signalling mediators in reproduction. It is widely accepted that anandamide (AEA) levels must be tightly regulated, and that a disturbance in AEA levels may impact decidual stability and regression. We have previously characterized the endocannabinoid machinery in rat decidual tissue and reported the pro-apoptotic action of AEA on rat decidual cells. Cyclooxygenase-2 (COX-2) is an inducible enzyme that plays a crucial role in early pregnancy, and is also a key modulator in the crosstalk between endocannabinoids and prostaglandins. On the other hand, AEA-oxidative metabolism by COX-2 is not merely a mean to inactivate its action, but it yields the formation of a new class of mediators, named prostaglandin-ethanolamides, or prostamides. In this study we found that AEA-induced apoptosis in decidual cells involves COX-2 metabolic pathway. AEA induced COX-2 expression through p38 MAPK, resulting in the formation of prostamide E2 (PME2). Our findings also suggest that AEA-induced effect is associated with NF-kB activation. Finally, we describe the involvement of PME2 in the induction of the intrinsic apoptotic pathway in rat decidual cells. Altogether, our findings highlight the role of COX-2 as a gatekeeper in the uterine environment and clarify the impact of the deregulation of AEA levels on the decidual remodelling process.
UCIBIO, REQUIMTE, Laboratory of Biochemistry, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Portugal.
M
M
Almada
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
F
F
Piscitelli
UCIBIO, REQUIMTE, Laboratory of Biochemistry, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Portugal.
B M
BM
Fonseca
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
V
V
Di Marzo
UCIBIO, REQUIMTE, Laboratory of Biochemistry, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Portugal.
G
G
Correia-da-Silva
UCIBIO, REQUIMTE, Laboratory of Biochemistry, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Portugal.
N
N
Teixeira
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001095:Arachidonic Acids / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003656:Decidua / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011247:Pregnancy; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D016328:NF-kappa B; D053284:Polyunsaturated Alkamides; C107684:prostaglandin E2 ethanolamide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C078814:anandamide
Anandamide; Apoptosis; COX-2; Decidualization; Prostamide E2; Signalling pathway