Circulating Activators of Peroxisome Proliferator-Activated Receptors Are Reduced in Preeclamptic Pregnancy

Waite, Leslie L.; Louie, Rachel E.; Taylor, Robert N.

doi:10.1210/jc.2004-0849

Cited by 73 publications

(66 citation statements)

References 32 publications

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“…In spontaneously hypertensive rats, there is reduced protein expression of placental PPAR-g (Mattace Raso et al, 2008). Waite et al (2005) demonstrated that serum extracts from pregnant women contained PPAR-g activators, and women with severe early-onset pre-clampsia had significantly reduced circulating PPAR-g activators compared with serum extracts from healthy pregnant women, suggesting that reduced PPAR-g activity may contribute to pre-clampsia . In contrast, Holdsworth-Carson et al (2010) examined placental expression of PPAR-g and demonstrated that placentas from women with pre-clampsia did not demonstrate any differences in mRNA or protein expression of PPAR-g compared with healthy controls (HoldsworthCarson et al, 2010).…”

Section: Pre-eclampsiamentioning

confidence: 97%

PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In recent years, evidence has linked PPARs to playing an integral role in pregnancy; specifically, PPAR-b and PPAR-g have been shown to play an integral role in placentation, with PPAR-g additionally serving to regulate trophoblast differentiation. Recent evidence has shown that PPAR-g expression is altered in many complications of pregnancy such as intrauterine growth restriction (IUGR), preterm birth, pre-clampsia and gestational diabetes. Thus, at present, accumulating evidence from the literature suggests both a pivotal role for PPAR-g in the progression of a healthy pregnancy and the possibility that PPAR-g may act as a therapeutic target in complicated pregnancies. This review aims to provide a succinct and comprehensive assessment of the role of PPAR-g in normal pregnancy and pregnancy complications, and finally its potential as a therapeutic target in the treatment and/or prevention of adverse pregnancy outcomes. AbbreviationsET-1, endothelin-1; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IKK, IkB kinase; RXR, retinoid X receptor; SO, superoxide; TXA2, thromboxane A2; VCAM-1, vascular adhesion molecule-1

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Section: Pre-eclampsiamentioning

confidence: 97%

PPAR‐γ – a possible drug target for complicated pregnancies

McCarthy

Delany

Kenny

et al. 2013

British J Pharmacology

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“…10 In addition, recent data have demonstrated that serum concentrations of endogenous agonists of PPAR-␥ are significantly reduced in women with severe early onset preeclampsia compared with healthy pregnant women. 11 In contrast, Holdsworth-Carson et al 12 demonstrated that placentas from women with preeclampsia did not exhibit any changes in either PPAR-␥ activity or placental expression of PPAR-␥ mRNA and PPAR-␥ protein, thus whether aberrant PPAR-␥ activity is involved in the development of pregnancies complicated by hypertension is not known. Furthermore, because of the limitations of conducting studies in pregnant women, and the embryonic lethality of homozygous PPAR-␥ receptor gene knockout in rodents, 9 the functional role of PPAR-␥ in normal pregnancy remains unclear.…”

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confidence: 97%

Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia

et al. 2011

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Abstract-Preeclampsia, a major cause of maternal and perinatal mortality and morbidity, is thought to be attributed, in part, to impaired trophoblast invasion. Peroxisome proliferator-activated receptors are ligand-activated transcription factors expressed in trophoblasts, which regulate the expression of a number of genes involved in cell differentiation and proliferation. We investigated the effect of the administration of a peroxisome proliferator-activated receptor-␥ antagonist during uncomplicated pregnancy in rats. Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the peroxisome proliferator-activated receptor-␥-specific antagonist, T0070907 (1 mg/kg per day from gestational days 11-15). Rats treated with T0070907 developed key features of preeclampsia, including elevated mean arterial blood pressure, proteinuria, endothelial dysfunction, reduced pup weight, and increased platelet aggregation. T0070907-treated rats had reduced plasma vascular endothelial growth factor and increased plasma soluble fms-like tyrosine kinase 1. Furthermore, increases in total placental soluble fms-like tyrosine kinase 1 mRNA and fms-like tyrosine kinase 1 protein were also demonstrated, suggesting the placenta as the main contributor to the increased circulating levels of soluble fms-like tyrosine kinase 1. The labyrinthine trophoblast in the placentas of T0070907-treated rats were less differentiated, had increased cellular proliferation, and were strongly immunopositive for CD-31 staining, indicating adaptive angiogenesis. The present study suggests that peroxisome proliferator-activated receptor-␥ may play a pivotal role in the progression of a healthy pregnancy and may critically regulate the risk of preeclampsia. These findings have important implications regarding the underlying etiology of preeclampsia and potential therapeutic targets. (Hypertension. 2011;58:882-887.) • Online Data Supplement Key Words: peroxisome proliferator activated receptor-␥ Ⅲ T0070907 Ⅲ preeclampsia Ⅲ vascular dysfunction P reeclampsia is a major cause of maternal and perinatal mortality and morbidity worldwide causing Ϸ15% of all direct maternal deaths and mediating a 5-fold increase in perinatal mortality. 1 Although the underlying etiology of preeclampsia is poorly understood, this condition is characterized by a relatively hypoperfused placenta, which stimulates the maternal response manifesting as hypertension, vascular dysfunction, and a pro-oxidant state. 2 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of a number of genes involved in cell differentiation and proliferation. 3 PPAR-␥ plays a predominant role in normal vascular function 4,5 and in the differentiation of labyrinthine trophoblast lineages, 6 which, along with the fetal endothelium, form the vascular exchange interface with maternal blood. 7 Homozygous PPAR-␥-deficient embryos die because of placental dysfunction, 8 and PPAR-␥ null placentas develo...

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“…4 PPAR-␥ plays a predominant role in normal vascular function 5 and in the differentiation of labyrinthine trophoblast lineages, 6 which, along with the fetal endothelium, form the vascular exchange interface with maternal blood. 7 A reduction in the placental expression of PPAR-␥ activators has been demonstrated in some women who develop severe preeclampsia, 8 and significantly higher PPAR-␥ DNA binding activity has been demonstrated in placentas from women with both intrauterine growth restriction and preeclampsia. 9 To investigate the role of PPAR-␥ as a potential therapeutic target for preeclampsia, we administered the PPAR-␥ agonist, rosiglitazone, to rats that had undergone reduced uterine perfusion pressure (RUPP) surgery.…”

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confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

et al. 2011

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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-␥ (PPAR-␥) 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-␥ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-␥ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-␥ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tinprotoporphyrin 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-␥ 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.) • Online Data SupplementKey Words: peroxisome proliferator-activated receptor-␥ Ⅲ preeclampsia Ⅲ reduced uterine perfusion pressure Ⅲ hypertension Ⅲ heme oxygenase 1 Ⅲ vascular dysfunction P reeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide, causing Ϸ15% of all direct maternal deaths and mediating a 5-fold increase in perinatal mortality. 1 Although the underlying etiology of preeclampsia is poorly understood, it is characterized by a relatively hypoperfused placenta, which stimulates the maternal response manifesting as hypertension, vascular dysfunction, alterations in platelet aggregation, and a pro-oxidant state. 2 There is currently no effective pharmacological intervention available for the treatment of preeclampsia, and, consequently, pregnancies are often delivered preterm for maternal benefit, imposing the challenges of iatrogenic prematurity on the fetus. 3 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of a number of genes involved in cell differentiation and proliferation. 4 PPAR-␥ plays a predominant role in normal vascular function 5 and in the differ...

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Circulating Activators of Peroxisome Proliferator-Activated Receptors Are Reduced in Preeclamptic Pregnancy

Cited by 73 publications

References 32 publications

PPAR‐γ – a possible drug target for complicated pregnancies

PPAR‐γ – a possible drug target for complicated pregnancies

Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

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