title: Peroxisome proliferator-activated receptor-γ as a potential therapeutic target in the treatment of preeclampsia.
abstract: Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-γ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-γ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-γ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-γ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.
authors.affiliation: Anu Research Centre, University College Cork, Cork University Maternity Hospital, Wilton, Cork, Ireland. fergusmccarthy@gmail.com
authors.forename: Fergus P
authors.initials: FP
authors.lastname: McCarthy
authors.forename: Sascha
authors.initials: S
authors.lastname: Drewlo
authors.forename: John
authors.initials: J
authors.lastname: Kingdom
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Johns
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Walsh
authors.forename: Louise C
authors.initials: LC
authors.lastname: Kenny
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D008665:Metalloporphyrins / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D008665:Metalloporphyrins; D047495:PPAR gamma; D011524:Protoporphyrins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C032628:tin protoporphyrin IX