HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

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.

Keywords: cardiomyopathy; embryopathy; fetal programing; heart development; hypoxia-inducible factor 1.

Figure 1

Oxygen dependent regulation of HIF-1α. In normoxic conditions, the HIF-1α protein is recognized by prolyl hydroxylase proteins (PHD), which hydroxylate prolines (OH) in the oxygen-dependent degradation domain. The hydroxylated prolines are recognized by the von Hippel-Lindau protein (VHL) and ubiquitinated (Ub) for degradation by the proteasome. In hypoxic conditions, HIF-1α and HIF-1β are translocated to the nucleus, where they form a heterodimer, bind to the hypoxia responsive element (HRE) and function as a transcription factor.

Figure 2

Heart development. (A) Cardiac progenitors form crescent shaped primary and secondary heart fields (PHF and SHF). (B)The primary heart field then forms the primary heart tube. The future outflow tract (OFT) is in the anterior part, future atria (A) are in the posterior part, and future ventricles (V) are in the middle of the tube. Cells from SHF populate the anterior and posterior parts of the tube. (C, D) The tube undergoes a process of looping, during which ventricles and atria are formed. The right ventricle (RV), left and right atria (LA and RA), and OFT are formed by SHF cells, the left ventricle (LV) is formed by PHF cells. During the process of septation of the ventricles, the muscular part of the interventricular septum (IVS) grows from the bases of the ventricles and connects with the remodeled endocardial cushion (ECC) in the atrioventricular canal. Similarly, the interatrial septum grows from the roof of the atria. Cardiac neural crest cells (CNCCs), migrating from the neural tube, contribute to the remodeling of the OFT. The proepicardial organ (PEO) is first formed on the ventral side of the future atria and through the process of looping is later positioned dorsally to the heart. The cells from the PEO migrate to the heart tube and form the epicardium (Epi). (E) The OFT is septated into the aorta (Ao) and pulmonary truncus (Pul) in the final step of heart development.

Figure 3

Schematic summary of HIF-1 signaling in hypoxia and diabetes. Under normoxia, glucose is metabolized to pyruvate and then the pyruvate dehydrogenase complex converts pyruvate to acetyl-CoA, which enters the TCA cycle, and NADH and FADH₂ are generated. Electrons derived from NADH and FADH₂ are utilized by the electron transport chain to generate ATP. Under hypoxia, HIF-1 activates glycolytic genes as a critical step of metabolic adaptation to hypoxia. HIF-1 induces anaerobic glycolysis by mediating the expression of pyruvate dehydrogenase kinase 1 (PDK1), which inhibits pyruvate dehydrogenase (PDH) and induces conversion of pyruvate to lactate. Under diabetes, 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 ROS production. The production of ROS is induced by oxidative stress due to the increased ratio of NADH/NAD⁺, and by AGE via signaling through its receptor (RAGE). ROS, ChREBP, and pseudohypoxia induce transcription of Hif1a mRNA. However, in the diabetic environment, HIF-1 signaling is negatively affected via modification of its coactivator p300, and by HIF-1α protein modifications.

Figure 4

Effects of diabetes on the heart. Diabetes leads to systemic hyperglycemia and hyperglycemia increases tissue hypoxia. HIF-1 signaling is altered due to the changes in HIF-1α transactivation and HIF-1α protein modifications. Dysregulation of cardiac HIF-1 signaling is associated with an increased risk of diabetic embryopathy, adverse long-term outcomes for the offspring, and diabetic cardiomyopathy.