Newborn hypoxia/anoxia inhibits cardiomyocyte proliferation and decreases cardiomyocyte endowment in the developing heart: role of endothelin-1.

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.

Differential expression of microRNAs in ischemic heart disease.

Recent studies provide evidence that ischemic preconditioning (IP) and ischemia/reperfusion (IR) injury lead to altered expression of microRNAs (miRNAs) that affect the survival and recovery of cardiomyocytes. These endogenous ∼22-nucleotide noncoding RNAs negatively regulate gene expression via degradation and translational inhibition of their target mRNAs. miRNAs are involved in differentiation, proliferation, electrical conduction, angiogenesis and apoptosis. These pathways can lead to physiological and pathological adaptations. This review intends to explore several facets of miRNA expression and the underlying mechanisms involved in IR injury, as well as IP as a cardioprotective strategy. In addition, we will investigate miRNA interaction with the renin-angiotensin system and the potential use of miRNAs in developing sensitive biomarkers for cardiovascular disease.

Binucleation of cardiomyocytes: the transition from a proliferative to a terminally differentiated state.

Cardiomyocytes possess a unique ability to transition from mononucleate to the mature binucleate phenotype in late fetal development and around birth. Mononucleate cells are proliferative, whereas binucleate cells exit the cell cycle and no longer proliferate. This crucial period of terminal differentiation dictates cardiomyocyte endowment for life. Adverse early life events can influence development of the heart, affecting cardiomyocyte number and contributing to heart disease late in life. Although much is still unknown about the mechanisms underlying the binucleation process, many studies are focused on molecules involved in cell cycle regulation and cytokinesis as well as epigenetic modifications that can occur during this transition. Better understanding of these mechanisms could provide a basis for recovering the proliferative capacity of cardiomyocytes.