Metabolic Adaptation of the Fetal and Postnatal Ovine Heart: Regulatory Role of Hypoxia-Inducible Factors and Nuclear Respiratory Factor-1

Abstract

Numerous metabolic adaptations occur in the heart after birth. Important transcription factors that regulate expression of the glycolytic and mitochondrial oxidative genes are hypoxia-inducible factors (HIF-1α and -2α) and nuclear respiratory factor-1 (NRF-1). The goal of this study was to examine expression of HIF-1α, HIF-2α, and NRF-1 and the genes they regulate in pre- and postnatal myocardium. Ovine right and left ventricular myocardium was obtained at four time points: 95 and 140 d gestation (term = 145 d) and 7 d and 8 wk postnatally. Steady-state mRNA and protein levels of HIF-1α and NRF-1 and protein levels of HIF-2α were measured along with mRNA of HIF-1α-regulated genes (aldolase A, α- and β-enolase, lactate dehydrogenase A, liver and muscle phosphofructokinase) and NRF-1-regulated genes (cytochrome c, Va subunit of cytochrome oxidase, and carnitine palmitoyltransferase I ). HIF-1α protein was present in fetal myocardium but dropped below detectable levels at 7 d postnatally. HIF-2α protein levels were similar at the four time points. Steady-state mRNA levels of α-enolase, lactate dehydrogenase A, and liver phosphofructokinase declined significantly postnatally. Aldolase A, β-enolase, and muscle phosphofructokinase mRNA levels increased postnatally. Steady-state mRNA and protein levels of NRF-1 decreased postnatally in contrast to the postnatal increases in cytochrome c, subunit Va of cytochrome oxidase, and carnitine palmitoyltransferase I mRNA levels. The in vivo postnatal regulation of enzymes encoding glycolytic and mitochondrial enzymes is complex. As transactivation response elements for the genes encoding metabolic enzymes continue to be characterized, studies using the fetal-to-postnatal metabolic transition of the heart will continue to help define the in vivo role of these transcription factors.