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

• Published in: The FASEB journal 2020-12, Vol.34 (12), p.16504-16515
• Main Authors: Itani, Nozomi, Skeffington, Katie L., Beck, Christian, Niu, Youguo, Katzilieris‐Petras, Georgios, Smith, Nicola, Giussani, Dino A.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; cardiovascular disease; Chickens - metabolism; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - metabolism; Female; fetus; Heart - drug effects; hypoxia; Hypoxia - drug therapy; Hypoxia - metabolism; Nitric Oxide - metabolism; Oxidative Stress - drug effects; Pravastatin - pharmacology; Pregnancy; Protective Agents - pharmacology; statins
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202001743R

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% O2) 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.