CARDIAC CHARACTERISTICS IN COPPER DEFICIENCY

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DESCRIPTION (Principal Investigator's Abstract): Cardiac hypertrophy is observed in several animal species fed copper deficient diets. Some of the changes resemble human cardiac pathologies. Determining the mechanism(s) by which cardiac hypertrophy occurs in the copper deficient rat is the long-term objective of this study. A second objective is to determine the extent and processes by which copper repletion reverses hypertrophy. The approach is to study both the myocardium and valves from histological and biochemical aspects and to relate these changes in both depleted and repleted states to potential alterations in organ function and energy charge. A polypeptide of approximately 23 K molecular weight appears to be diminished in deficient rats and could be subunit III of cytochrome C oxidase. Decreased activity of this enzyme and alteration of mitochondria are present in some human heart diseases. Using microsequencing techniques, the polypeptide present in controls but absent in deficient rats will be identified and the regulation of this polypeptide as a function of both copper deficiency and repletion studies using radiotracers and molecular biology techniques. The rate of protein synthesis and degradation and whether copper regulates the 23 K at the transcriptional level will be studied. Any reversal with copper repletion of the cardiac damage observed in copper deficiency will be evaluated using transmission electron microscopy. In addition to muscle alterations, valve structure is altered in copper deficiency as evidenced by a less dense connective tissue network. While the histological structure of the collagen fibril is not altered, the rate of collagen synthesis may be changed. Decreased or defective connective tissue of floppy heart valves is a problem in some types of human disorders such as Ehlers-Danlos and Marfan syndromes. Deficiency and repletion studies may reveal some effect upon both rate of collagen synthesis and isoform expression and will be evaluated using techniques already described. These studies may also have clinical applications for those individuals who may possess some form of defective copper metabolism or deficiency.