Protective effects of pravastatin on the embryonic cardiovascular system during hypoxic development

Abstract

The use of statins in complicated pregnancy is being considered, as they protect endothelial function in the mother and placenta. However, whether statins affect cardiovascular function in the fetus is completely unknown. Here, we have determined the effects of pravastatin and underlying mechanisms on the cardiovascular system of the hypoxic chicken embryo, a model system that permits the direct effects of pravastatin on the developing offspring to be isolated independently of additional effects on the mother and/or placenta. Chicken embryos were incubated under normoxia or hypoxia (14% O 2) from day 1 ± pravastatin (1 mg/kg/d) from day 13 of incubation (term is 21 days). On day 19 of incubation, hearts and vessels were isolated to determine changes in the cardiovascular structure and function. The data show that pravastatin protected the hypoxic chicken embryo against impaired cardiovascular dysfunction. Mechanisms involved in this protection included reduced oxidative stress, enhanced NO bioavailability, restored antioxidant defenses and normalized protein expression of RhoA in the embryonic heart, and improved NO-dependent vasodilator mechanisms in the peripheral circulation. Therefore, we show that the treatment of the chronically hypoxic chicken embryo with pravastatin from day 13 of incubation, equivalent to ca. 25 weeks of gestation in human pregnancy, has direct beneficial effects on the embryonic cardiovascular system. Therefore, pravastatin may be a candidate for human clinical translation to rescue fetal cardiovascular dysfunction in risky pregnancy. 2 | ITANI eT Al.

Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

“…Several studies have shown that antioxidants can prevent fetal cardiac remodeling and dysfunction in adulthood, such as maternal treatment with vitamin C, allopurinol, statins, MitoQ, and melatonin. 9,11,[36][37][38][39][40][41] Antioxidant protection on the offspring of hypoxic pregnancy manifests in several ways, including enhanced antioxidant capacity, improvements in transplacental oxygenation, diminished endothelial dysfunction, and normalization of arterial blood pressure. 38 Interestingly, the protective effects are enhanced if mitochondria-targeted antioxidants, such as MitoQ, are used, 39 suggesting ROS production from the mitochondria may play a significant role in programming cardiac dysfunction.…”

“…In this respect, maternal antioxidant treatment is emerging as a promising new approach. Several studies have shown that antioxidants can prevent fetal cardiac remodeling and dysfunction in adulthood, such as maternal treatment with vitamin C, allopurinol, statins, MitoQ, and melatonin 9,11,36–41 . Antioxidant protection on the offspring of hypoxic pregnancy manifests in several ways, including enhanced antioxidant capacity, improvements in transplacental oxygenation, diminished endothelial dysfunction, and normalization of arterial blood pressure 38 .…”

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy

“…Therefore, there is interest in identifying alternative maternal therapy with improved human translational potential. Recent studies have focussed either on increasing oxygen delivery, to avoid oxidative stress in the first instance, 14,15 or using alternative antioxidant therapy 16‐18 …”

Fetal toxicity associated with statins: A systematic review and meta-analysis

“…In contrast with the general perception and recommendations that treatment with statins in pregnancy and even in the preconception period should be avoided, most recent data indicate that statins could have beneficial effects in pregnancy. For example, it has been reported recently that statins might protect endothelial function in the mother and placenta thus rescuing fetal cardiovascular dysfunction in complicated pregnancies 46 . It seems also that statins might be useful (mainly pravastatin) for preventing or treating preeclampsia 47 .…”