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McCarthy, FP,Drewlo, S,Kingdom, J,Johns, EJ,Walsh, SK,Kenny, LC;
Peroxisome Proliferator-Activated Receptor-gamma as a Potential Therapeutic Target in the Treatment of Preeclampsia
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peroxisome proliferator-activated receptor-gamma preeclampsia reduced uterine perfusion pressure hypertension heme oxygenase 1 vascular dysfunction UTERINE PERFUSION-PRESSURE PPAR-GAMMA HEME OXYGENASE-1 VASCULAR DYSFUNCTION ENDOTHELIAL FUNCTION PLACENTAL ISCHEMIA REPERFUSION INJURY HUMAN TROPHOBLAST PREGNANT RATS EXPRESSION
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-gamma (PPAR-gamma) 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-gamma agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-gamma agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-gamma 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-gamma 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. (Hypertension. 2011;58:280-286.)
DOI 10.1161/HYPERTENSIONAHA.111.172627
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