Abstract
The heart is able to metabolize any substrate, depending on its availability, to satisfy its energy requirements. Under normal physiological conditions, about 95% of ATP is produced by oxidative phosphorylation and the rest by glycolysis. Cardiac metabolism undergoes reprograming in response to a variety of physiological and pathophysiological conditions. Hypoxia-inducible factor 1 (HIF-1) mediates the metabolic adaptation to hypoxia and ischemia, including the transition from oxidative to glycolytic metabolism. During embryonic development, HIF-1 protects the embryo from intrauterine hypoxia, its deletion as well as its forced expression are embryonically lethal. A decrease in HIF-1 activity is crucial during perinatal remodeling when the heart switches from anaerobic to aerobic metabolism. In the adult heart, HIF-1 protects against hypoxia, although its deletion in cardiomyocytes affects heart function even under normoxic conditions. Diabetes impairs HIF-1 activation and thus, compromises HIF-1 mediated responses under oxygen-limited conditions. Compromised HIF-1 signaling may contribute to the teratogenicity of maternal diabetes and diabetic cardiomyopathy in adults. In this review, we discuss the function of HIF-1 in the heart throughout development into adulthood, as well as the deregulation of HIF-1 signaling in diabetes and its effects on the embryonic and adult heart.
Highlights
Oxygen is a key factor in mammalian energy metabolism [1]
Metabolic stress is induced by: an increased ratio of NADH/NAD+ due to an increased flux of glucose through the polyol pathway resulting in pseudohypoxia; increased expression of peroxisome proliferator-activated receptor alpha (PPARα), which induces fatty acid utilization and oxidation; increased fatty acid oxidation leading to the production of acetyl-CoA; increased production of advanced glycation end products (AGE), which leads to the irreversible modification of proteins; induction of the carbohydrate response element binding protein (ChREBP); and increased reactive oxygen species (ROS) production
Utilization of fatty acids (FA) is regulated by peroxisome proliferator-activated receptor α (PPARα), which targets most of the genes of the fatty acid oxidation pathway [102], is inhibited by Hypoxia-inducible factor 1 (HIF-1) [103] and its cardiac overexpression leads to inhibition of glucose uptake, mimicking the effect of diabetes [104]
Summary
Oxygen is a key factor in mammalian energy metabolism [1]. In normoxic conditions, cells generate adenosine triphosphate (ATP) through the mitochondrial electron transport chain, which requires oxygen as a terminal electron acceptor. We will summarize the role of HIF-1 signaling in the responses to hypoxia in heart development and aberrant HIF-1 regulation in diabetic conditions. Constitutive cardiac-specific over-expression of Hif1a leads to changes in cellular metabolism and increased glucose utilization [55], resulting in cardiomyopathy in aging mice.
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