In the developing heart, cardiomyocytes undergo terminal differentiation during a critical window around birth.
Hypoxia is a major stress to preterm infants, yet its effect on the development and maturation of the heart remains unknown. We tested the hypothesis in a rat model that newborn
anoxia accelerates cardiomyocyte terminal differentiation and results in reduced cardiomyocyte endowment in the developing heart via an endothelin-1-dependent mechanism. Newborn rats were exposed to
anoxia twice daily from postnatal day 1 to 3, and hearts were isolated and studied at postnatal day 4 (P4), 7 (P7), and 14 (P14).
Anoxia significantly increased HIF-1α
protein expression and pre-proET-1
mRNA abundance in P4 neonatal hearts. Cardiomyocyte proliferation was significantly decreased by
anoxia in P4 and P7, resulting in a significant reduction of cardiomyocyte number per heart weight in the P14 neonates. Furthermore, the expression of
cyclin D2 was significantly decreased due to
anoxia, while p27 expression was increased.
Anoxia has no significant effect on cardiomyocyte binucleation or myocyte size. Consistently, prenatal
hypoxia significantly decreased cardiomyocyte proliferation but had no effect on binucleation in the fetal heart. Newborn administration of PD156707, an ETA-receptor antagonist, significantly increased cardiomyocyte proliferation at P4 and cell size at P7, resulting in an increase in the heart to
body weight ratio in P7 neonates. In addition, PD156707 abrogated the
anoxia-mediated effects. The results suggest that
hypoxia and
anoxia via activation of
endothelin-1 at the critical window of heart development inhibits cardiomyocyte proliferation and decreases myocyte endowment in the developing heart, which may negatively impact cardiac function later in life.