*Center for Cardiovascular Research, Department of Medicine; Departments of Molecular Biology & Pharmacology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110; fDepartment of Medicine, Baylor College of Medicine, Houston, Texas 77030
The adult mammalian heart is highly specialized for efficient and high-capacity energy production to meet the diverse physiologic demands of the postnatal environment. In contrast to the fetal heart, which relies largely on glucose, the adult heart is programmed to rely on multiple energy sources. Although the postnatal heart continues to utilize glucose, the primary source of ATP is the mitochondrial fatty acid oxidation (FAO) pathway (Bing 1955; Neely et al. 1972; Schulz 1991). The expression of FAO pathway enzymes is induced following birth via de-velopmentally programmed nuclear gene regulatory events. The relative importance of glucose and fatty acids as fuel sources for the adult heart is a function of developmental, physiologic, and dietary contexts (Lockwood and Bailey 1970; Neely et al. 1972; Schulz 1991). For example, energy production in the fetal heart is primarily via glycolysis because mitochondrial oxidative capacity is limited. Furthermore, although the energy demands of the fully developed heart are mainly met by the oxidation of fats, glucose utilization is important in postprandial states and with sudden increases in hemodynamic load. Thus, the normal adult heart exhibits "plasticity" in its energy substrate choices.
Evidence has emerged that the normal balance of myocardial energy substrate utilization is compromised in several common cardiovascular disease states (Fig. 1). For example, the extraordinary capacity of the heart to ca-tabolize fatty acids within mitochondria is diminished in pathologic forms of cardiac hypertrophy (Bishop and Altschuld 1970; Taegtmeyer and Overturf 1988; Christe and Rodgers 1994) and in the hypoxic or ischemic heart (Fig. 1) (Abdel-aleem et al. 1998; Rumsey et al. 1999). Conversely, glucose utilization is severely reduced in the diabetic heart such that it relies almost exclusively on FAO (Rodrigues et al. 1995; Stanley et al. 1997; Belke et al. 2000). Do these metabolic "switches" serve an adaptive function? For example, does the shift from mito-chondrial FAO to glucose utilization in the hypoxic or hypertrophied heart reduce oxygen consumption costs as an adaptive response? Do such changes become maladaptive, leading to heart failure? Similarly, does the reduction in glucose utilization by the diabetic heart lead to the dysfunction and increased cardiovascular morbidity of the diabetic population? Recent studies in the field of cardiac metabolism have begun to address these and related questions. The answers should lead to the development of novel therapeutic strategies aimed at modulating cardiac metabolism in common diseases of the myocardium.
This review covers three topics related to the control of cardiac mitochondrial function in the normal and diseased heart. First, current knowledge of a gene regulatory program involved in the developmental maturation of the cardiac mitochondrial FAO pathway is reviewed. The control of the cardiac mitochondrial FAO by the nuclear receptor peroxisome proliferator-activated receptor a (PPARa) and the retinoid X receptor (RXR) will serve as the starting point, followed by a description of recently discovered links to the program of mitochondrial biogenesis. Second, mechanisms leading to derangements in the PPARa-mediated control of cardiac energy metabolism in the hypertrophied, hypoxic, and failing heart are summarized. Third, the molecular regulatory events responsible for altered energy metabolism in the diabetic heart are reviewed, and a mouse model of diabetic cardiomyopathy is described.
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