Oxygen, oxidative stress, hypoxia, and heart failure

Abstract

A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.The mammalian heart is an obligate aerobic organ. At a resting pulse rate, the heart consumes approximately 8-15 ml O 2 /min/100 g tissue. This is significantly more than that consumed by the brain (approximately 3 ml O 2 /min/100 g tissue) and can increase to more than 70 ml O 2 /min/100 g myocardial tissue during vigorous exercise (1, 2). Mammalian heart muscle cannot produce enough energy under anaerobic conditions to maintain essential cellular processes; thus, a constant supply of oxygen is indispensable to sustain cardiac function and viability. The story of oxygen in the heart is complex, however, and goes well beyond its role in energy metabolism.Oxygen is a major determinant of myocardial gene expression, and as myocardial O 2 levels decrease, either during isolated hypoxia or ischemia-associated hypoxia, gene expression patterns in the heart are significantly altered (3). Oxygen participates in the generation of NO, which plays a critical role in determining vascular tone, cardiac contractility, and a variety of additional parameters. Oxygen is also central in the generation of reactive oxygen species (ROS), which can participate as benevolent molecules in cell signaling processes or can induce irreversible cellular damage and death. Oxygen is thus both vital and deleterious (4). The role of oxygen in myocardial energetics and metabolismThe heart can utilize a variety of metabolic fuels, including fatty acids, glucose, lactate, ketones, and amino acids. In the fed state, fatty acids are the preferred fuel, accounting for up to 90% of the total acetyl-CoA provided to cardiac mitochondria (5). Fatty acids are metabolized by β-oxidation, producing acetyl-CoA, NADH, and FADH 2 . The acetyl-CoA enters the Krebs cycle, producing more NADH and FADH 2 . Glucose is metabolized initially via the glycolytic pathway, producing a relatively small amount of ATP and also pyruvate, which enters the Krebs cycle, producing NADH and FADH 2 . In the absence of oxygen, the total amount of energy produced by these processes is insufficient to meet cardiac needs. The cardiac energy requirement is met, however, by entry of the resultant NADH and FADH 2 into the electron transport chain, which generates ATP by oxidative phosphorylation in the mitochondria. Oxygen serves as the terminal electron acceptor in the electron transport chain, and in the absence of sufficient oxygen, electron transport ceases and cardiac energy demands are not met (Figure 1). Generation and counterbalancing of ROSROS can be formed in the heart by a ...

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