Abstract
Heme oxygenase (Hmox) is an endogenous system that offers protection against placental cytotoxic damage associated with preeclampsia. The Hmox1/carbon monoxide (CO) pathway inhibits soluble Flt-1 (sFlt-1) and soluble Endoglin (sEng). More importantly, statins induce Hmox1 and suppress the release of sFlt-1 and sEng; thus, statins and Hmox1 activators are potential novel therapeutic agents for treating preeclampsia. The contribution of the Hmox system to the pathogenesis of preeclampsia has been further indicated by the incidence of preeclampsia being reduced by a third in smokers, who had reduced levels of circulating sFlt-1. Interestingly, preeclamptic women exhale less CO compared with women with healthy pregnancies. Hmox1 is reduced prior to the increase in sFlt-1 as Hmox1 mRNA expression in the trophoblast is decreased in the first trimester in women who go on to develop preeclampsia. Induction of Hmox1 or exposure to CO or bilirubin has been shown to inhibit the release of sFlt-1 and sEng in animal models of preeclampsia. The functional benefit of statins and Hmox1 induction in women with preeclampsia is valid not only because they inhibit sFlt-1 release, but also because statins and Hmox1 are associated with anti-apoptotic, anti-inflammatory, and anti-oxidant properties. The StAmP trial is the first randomized control trial (RCT) evaluating the use of pravastatin to ameliorate severe preeclampsia. This proof-of-concept study will pave the way for future global RCT, the success of which will greatly contribute to achieving the United Nations Millennium Development Goals (MDG4 and MDG5) and offering an affordable and easily accessible therapy for preeclampsia.
Highlights
Preeclampsia is characterized by the de novo onset of hypertension and proteinuria after 20 weeks of gestation
The pharmacological induction of Hmox1 in human placental villous explants was shown to offer placental cytoprotection (Ahmed et al, 2000). This endogenous protective system could be impaired and it is possible that the decreased expression or the loss of Heme oxygenase (Hmox) activity might contribute to the maternal endothelial dysfunction observed
The functional benefit of Hmox in preeclampsia has gained increasing importance, in particular, after the publication demonstrating that the adenoviral overexpression of Hmox-1 or direct exposure to carbon monoxide (CO) reduce both basal and vascular endothelial growth factor (VEGF)-E-stimulated soluble Flt-1 (sFlt-1) release from human umbilical vein endothelial cells (HUVEC), while siRNA-mediated Hmox1 knockdown increases sFlt-1 release (Cudmore et al, 2007)
Summary
Preeclampsia is characterized by the de novo onset of hypertension and proteinuria after 20 weeks of gestation. An increase in inflammation is not associated with the increase in anti-angiogenic factors (Ramma et al, 2012) or disease severity (Ozler et al, 2012) Together, these do indicate that the increase in inflammation occurs as a consequence of preeclampsia and that it is not the cause of the disorder (Ramma and Ahmed, 2011). These do indicate that the increase in inflammation occurs as a consequence of preeclampsia and that it is not the cause of the disorder (Ramma and Ahmed, 2011) To date, it seems that therapeutic strategies aimed at addressing the angiogenic imbalance in preeclampsia will provide the most promising outcome
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