Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1

Introduction: Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent miscarriages. Here, we investigated the effects of pravastatin on HO-1 expression, placental development, and fetal survival in mice with a partial HO-1 deficiency. Methods: At E14.5, untreated pregnant wild-type (WT, n=13-18), untreated HO-1(+/-) (Het, n=6-9), and Het mice treated with pravastatin (Het+ Pravastatin, n=12-14) were sacrificed. Numbers of viable fetuses/resorbed concepti were recorded. Maternal livers and placentas were harvested for HO activity. Hematoxylin and eosin (H & E) and CD31 immunohistochemical staining were performed on whole placentas. Results: Compared with WT, HO activity in Het livers (65 +/- 18%, P<0.001) and placentas (74 +/- 7%, P<0.001) were significantly decreased. Number of viable fetuses per dam was significantly lower in Untreated Het dams (6.0 +/- 2.2) compared with WT (9.1 +/- 1.4, P<0.01), accompanied by a higher relative risk (RR) for concepti resorption (17.1, 95% CI 4.0-73.2). In Hets treated with pravastatin, maternal liver and placental HO activity increased, approaching levels of WT controls (to 83 +/- 7% and 87 +/- 14%, respectively). The number of viable fetuses per dam increased to 7.7 +/- 2.5 with a decreased RR for concepti resorption (2.7, 95% CI 1.2-5.9). In some surviving Untreated Het placentas, there were focal losses of cellular architecture and changes suggestive of reduced blood flow in the labyrinth. These findings were absent in Het+ Pravastatin placentas. Discussion: Pravastatin induces maternal liver and placental HO activity, may affect placental function and improve fetal survival in the context of a partial deficiency of HO-1.