Therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia

• Published in: Journal of reproductive immunology 2014-03, Vol.101 (100), p.153-160
• Main Authors: Ramma, Wenda, Ahmed, Asif
• Format: Article
• Language: English
• Subjects: Animals; Carbon monoxide (CO); Disease Models, Animal; Female; Heme oxygenase-1 (Hmox1); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Obstetrics and Gynecology; Pre-Eclampsia - drug therapy; Preeclampsia; Pregnancy; Randomized Controlled Trials as Topic; Soluble Endoglin (sEng); Soluble Flt-1 (sFlt-1); Statins; Up-Regulation; Vascular endothelial growth factor (VEGF); Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 0165-0378; 1872-7603
• DOI: 10.1016/j.jri.2013.12.120

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.