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

McCarthy, Fergus P.; Drewlo, Sascha; Kingdom, John; Johns, Edward J.; Walsh, Sarah; Kenny, Louise C.

doi:10.1161/hypertensionaha.111.172627

Cited by 78 publications

(91 citation statements)

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“…17,[19][20][21][22][23][24][25][26]28,37,38 For instance, we verified increased systolic blood pressure, altered fetal biometrics, and glomerular endotheliosis in RUPP compared with sham-operated rats.…”

Section: Discussionmentioning

confidence: 93%

Lectin-Like Oxidized Low-Density Lipoprotein 1 Receptor in a Reduced Uteroplacental Perfusion Pressure Rat Model of Preeclampsia

et al. 2012

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Abstract-Preeclampsia is a major cause of maternal and fetal morbidity and mortality that has been associated with endothelial dysfunction attributed, in part, to dyslipidemia, an imbalance in angiogenic factors and oxidative stress. One of the many factors that have been shown to be elevated in women with preeclampsia is low-density lipoprotein (LDL) and the more oxidizable, small dense LDL, which can lead to increased vascular oxidative stress and decreased bioavailability of NO. Lectin-like oxidized LDL-1 receptor (LOX-1) is a specific receptor for oxidized LDL. We hypothesized that a reduction of placental perfusion using a rat model of reduced uteroplacental perfusion pressure would result in enhanced LOX-1 expression in the maternal vasculature causing impaired vascular endothelial function through the actions of increased superoxide production and decreased NO-mediated vasodilation. We demonstrated a significant increase in the expression of the LOX-1 receptor (4.3-fold; Pϭ0.002), endothelial NO synthase (2.7-fold; Pϭ0.001), and superoxide (Pϭ0.02) in thoracic aorta of the reduced uteroplacental perfusion pressure model, whereas maximal vasodilator function was modestly decreased (PϽ0.05). Endothelial-dependent vasodilator function was unaffected by either oxidized LDL or an LOX-1 receptor inhibitor in controls but was modestly increased in the presence of both oxidized LDL and the LOX-1 receptor inhibitor in reduced uteroplacental perfusion pressure (Pϭ0.03). In summary, we have shown that, in a rat model of preeclampsia, there is a dramatic increase in the expression levels of both the LOX-1 receptor and the endothelial NO synthase enzyme, along with evidence of increased superoxide production and subsequent modestly decreased endothelial function. (Hypertension. 2012;59:1014-1020.)Key Words: preeclampsia Ⅲ vascular function Ⅲ LOX-1 receptor Ⅲ oxidized LDL Ⅲ RUPP P reeclampsia is one of the most enduring and inadequately understood pathologies of pregnancy, which affects 5% to 8% of pregnancies and is a major cause of maternal and fetal morbidity and mortality.1,2 This almost uniquely human disorder is characterized by de novo hypertension Ͼ140/90 mm Hg after the 20th week of gestation accompanied by proteinuria more than ϩ2. Although the diagnosis is reasonably clear, the underlying causes remain obscure, likely because of the extreme complexity of this disorder. Interestingly, the only currently known cure for preeclampsia is removal of the placenta and, hence, delivery of the baby, suggesting a central role for this organ. It is thought that an underperfused placenta is responsible for the release of placental debris and multiple factors, which, in turn, causes the maternal syndrome.3,4 Indeed, preeclampsia has been associated with both increased systemic vascular resistance and endothelial dysfunction.One of the many factors that have been shown to be elevated in women with preeclampsia is low-density lipoprotein (LDL) and the more oxidizable, small dense LDL. 5-10Combined with a significant volume ...

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Section: Discussionmentioning

confidence: 93%

Lectin-Like Oxidized Low-Density Lipoprotein 1 Receptor in a Reduced Uteroplacental Perfusion Pressure Rat Model of Preeclampsia

et al. 2012

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“…The underlying decidual vasculopathy, established in early pregnancy, renders the placental villi poorly perfused, inducing static local hypoxia 76 or more likely a dynamic process of ischemia-reperfusion injury. 77 The GCM1 axis, which controls differentiation of both types of trophoblasts, is disrupted in severely preeclamptic placental villi to favor a reduction in syncytial fusion [78][79][80][81] and is accentuated by hypoxia-mediated degradation of GCM1. 82 Patchy areas of apoptosis, excess syncytial knot formation, and areas of necrosis are found in severe preeclamptic placental villi 83 and can be reproduced in vitro, respectively, by hypoxic culture 84 or hypoxia-reoxygenation 77 in cultured first-trimester placental villous explants.…”

Section: Placental Pathology Of Severe Pementioning

confidence: 99%

Is heparin a placental anticoagulant in high-risk pregnancies?

Kingdom

Drewlo

2011

Blood

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Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non-anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy. IntroductionA small subset of reproductive-aged women require anticoagulation in the context of a mechanical heart valve 1 or to prevent recurrent venous thromboembolism as in women with antiphospholipid syndrome. 2 When planning pregnancy, they mostly convert from an oral anticoagulant such as Coumadin to subcutaneous injections of heparin to avoid the potential embryopathy induced by transplacental passage of Coumadin. 3 By doing so, they expose themselves to relatively minor side effects such as skin bruising and, because heparin promotes bone loss, to the rare possibility of vertebral bone compression fractures and neurologic complications. 4 In this context heparin is a success story for women whose predecessors were counseled to avoid attempts at motherhood. More than 35 years ago the concept of placental anticoagulation was proposed for women in subsequent pregnancies after recurrent placental infarction. 5 Since then we have witnessed an exponential increase in the prescription of heparin to pregnant women for a wide variety of indications, based on a common theme that superior placental function can be attained via its anticoagulant properties. The fashion has spread widely according to claims that heparin promotes successful implantation after in vitro fertilization, 6,7 prevents recurrent miscarriages, 8 promotes better outcomes in the perinatal period, 9 and, finally, may be used vaginally to induce labor in full-term pregnancies. 10 A common aspect of these studies is the use of safer low molecular weight heparins (LMWHs) in prophylactic regimes that have a low risk of serious side effects when used over a relatively short duration of time in pregnancy. However, the current cost per pregnancy to prescribe prophylactic LMWH is ϳ $3000, a significant burden to uninsured women in countries, such as Canada, with variable employer-based drug plans. Ongoing use of such drugs for these indications in pregnancy therefore deserves more rigorous evidence. Recent impressive but negative trials are making progress by limiting the scope of use in women with recurrent miscarriage. Heparins are complex macromol...

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“…72,73 In models of cardiovascular disease, activation of PPAR restores vascular structure and endothelial function. 74 Its beneficial effects are mediated by upregulation of HO-1. 74 In experimental preeclampsia, the PPAR-agonist rosiglitazone ameliorates hypertension and endothelial dysfunction in a HO-1-dependent pathway.…”

Section: Carbon Monoxidementioning

confidence: 99%

“…74 Its beneficial effects are mediated by upregulation of HO-1. 74 In experimental preeclampsia, the PPAR-agonist rosiglitazone ameliorates hypertension and endothelial dysfunction in a HO-1-dependent pathway. 74 In conclusion, agents capable of HO induction are beneficial as therapeutic agents in experimental preeclampsia.…”

Section: Carbon Monoxidementioning

confidence: 99%

“…74 In experimental preeclampsia, the PPAR-agonist rosiglitazone ameliorates hypertension and endothelial dysfunction in a HO-1-dependent pathway. 74 In conclusion, agents capable of HO induction are beneficial as therapeutic agents in experimental preeclampsia. Statins and PPAR-agonists are HO-inducing agents and ameliorate hypertension, restore endothelial function, and lower sFlt1 in experimental preeclampsia.…”

Section: Carbon Monoxidementioning

confidence: 99%

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