Effects of Gestational Hypoxia on PGC1α and Mitochondrial Acetylation in Fetal Guinea Pig Hearts

Chronic intrauterine hypoxia is a significant pregnancy complication impacting fetal heart growth, metabolism, and mitochondrial function, contributing to cardiovascular programming of the offspring. PGC1 alpha (peroxisome proliferator-activated receptor gamma co-activator 1 alpha) is the master regulator of mitochondrial biogenesis. We investigated the effects of hypoxia on PGC1 alpha expression following exposure at different gestational ages. Time-mated pregnant guinea pigs were exposed to normoxia (NMX, 21% O-2) or hypoxia (HPX, 10.5% O-2) at either 25-day (early-onset) or 50-day (late-onset) gestation, and all fetuses were extracted at term (term = similar to 65-day gestation). Expression of nuclear PGC1 alpha, sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and mitochondrial sirtuin 3 (SIRT3) was measured, along with SIRT3 activity and mitochondrial acetylation of heart ventricles of male and female fetuses. Early-onset hypoxia increased (P<0.05) fetal cardiac nuclear PGC1 alpha and had no effect on mitochondrial acetylation of either growth-restricted males or females. Late-onset hypoxia had either no effect or decreased (P<0.05) PCC1 alpha expression in males and females, respectively, but increased (P<0.05) mitochondrial acetylation in both sexes. Hypoxia had variable effects on expression of SIRT1, AMPK, SIRT3, and SIRT3 activity depending on the sex. The capacity of the fetal heart to respond to hypoxia differs depending on the gestational age of exposure and sex of the fetus. Further, the effects of late-onset hypoxia on fetal heart function impose a greater risk to male than female fetuses, which has implications toward cardiovascular programming effects of the offspring.

Automated summary

Chronic intrauterine hypoxia affects fetal heart development and mitochondrial function, and the response varies depending on gestational age and fetal sex. PGC1 alpha plays a crucial role in mitochondrial biogenesis. This study found that early-onset hypoxia increased fetal cardiac nuclear PGC1 alpha expression, while late-onset hypoxia had variable effects on PGC1 alpha expression and increased mitochondrial acetylation. Hypoxia also affected the expression and activity of other mitochondrial regulators such as SIRT1, AMPK, and SIRT3, with sex-dependent differences. Late-onset hypoxia posed a greater risk to male fetuses in terms of heart function and cardiovascular programming effects.