Genetic modification of the heart: transgenic modification of cardiac lipid and carbohydrate utilization.

ABSTRACT

Many recent advances in cardiovascular research have been made possible by the use of transgenic technology. This review will discuss a number of mouse models where transgenic technology has been utilized to alter expression of genes involved in cardiac uptake and metabolism of either lipid or carbohydrate. Particular attention will be paid to the proteins which regulate (1) carbohydrate and lipid transport into cardiomyocytes and (2) the subsequent metabolic process which occur within the cytosol. These steps are important in determining substrate availability for mitochondrial oxidative metabolism. The heart relies predominantly on fatty acids as its major fuel supply, while glucose and lactate provide a small percentage. Under certain conditions, this balance becomes altered such that the heart relies more on glucose, as seen in pathological hypertrophy or may rely almost solely on fatty acids, as observed in cardiac tissue of animal models of diabetes. Initially this switch in metabolic substrate provides adequate energy to maintain normal cardiac function however with time diastolic dysfunction and cardiac failure often occur associated with depletion in high-energy phosphates. The creation of transgenic mice with altered expression of genes involved in carbohydrate and lipid metabolism have provided a unique insight into the fine balance which exits in the mouse heart to maintain energy status and cardiac function. The models discussed in this review define both transport and cytosolic metabolism of lipid and carbohydrate as key cellular processes in the regulation of cardiac function and the pathogenesis of cardiac disease.