15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) is a highly reactive cyclopentenone eicosanoid generated from the dehydration of cyclooxygenase(COX)-derived prostaglandin D2 (PGD2). We have obtained data supporting the contention that. In addition to the COX pathway, 15-d-PGJ2 can be generated from the dehydration of PGD2-like compounds, termed D2-isoprostanes (IsoPs), which are formed from the free radical-catalyzed peroxidation of arachidonic acid under settings of oxidative stress. This is relevant because 15-d-PGJ2 has been postulated as an important mediator of a wide variety of biological processes. Its diverse bioactivities are largely attributed to the presence of a reactive polyunsaturated carbonyl moiety on its prostane ring that is a substrate for Michael addition with thiol-containing biomolecules, such as glutathione and cysteine residues on proteins. 15-d-PGJ2 has been shown to possess anti-proliferative and pro-apoptotic activity. Some of its activity may relate to the observation that it is a ligand for peroxisome proliferator-activated receptor-gamma. Additionally, 15-d-PGJ2 has been reported to be present in significant amounts in human atherosclerotic lesions and to reside in foam cells, suggesting an important role for it in modulating inflammatory and apoptotic responses. Despite great interest in its bioactivity, the extent to which 15-d-PGJ2 is formed in vivo and the mechanisms that regulate its formation are unclear. The overall goal of the proposed research is to determine the extent to which 15-d-PGJ2 is formed in vivo and examine the mechanisms that regulate it formation. We hypothesize that both the COX and IsoP pathways contribute to the formation of 15-d-PGJ2 in vivo. To test this hypothesis, we will develop mass spectrometric methodologies to measure the major urinary metabolite of 15-d-PGJ2 as a biomarker of its endogenous production. The following specific aims are thus proposed: I.) Determine the metabolic fate of 15-d-PGJ2 in the rat and identify its major urinary metabolite;II.) Compare the metabolism of 15-d-PGJ2 in rats and humans;and III.) Examine the contributions of the COX and IsoP pathways to the formation of 15- d-PGJ2 in vivo. As a result of being generated through the COX and IsoP pathways in vivo, 15-d-PGJ2 may mediate various physiological and pathophysiological processes involved in inflammation and oxidant injury. It is clear that diseases associated with inflammation and/or oxidative injury, such as atherosclerosis, Alzheimer's disease, and cancer, pose a tremendous public health burden on our nation. In this context, studies examining the formation and metabolism of 15-d-PGJ2 will lay the foundation for understanding its role in the pathophysiology of these and related diseases.
| Hardy, Klarissa D; Cox, Brian E; Milne, Ginger L et al. (2011) Nonenzymatic free radical-catalyzed generation of 15-deoxy-?(12,14)-prostaglandin J?-like compounds (deoxy-J?-isoprostanes) in vivo. J Lipid Res 52:113-24 |
