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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #170533
Title: INCREASED CONTRACTILITY OF CARDIOMYOCYTES FROM COPPER-DEFICIENT RATS IS ASSOCIATED WITH UPREGULATION OF CARDIAC INSULIN-LIKE GROWTH FACTOR-I RECEPTOR

Author
item DONG, FENG - UNIV OF WYOMING
item ESBERB, LUCY - UNIV OF NORTH DAKOTA
item Roughead, Zamzam
item REN, JUN - UNIV OF WYOMING
item Saari, Jack

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/18/2005
Publication Date: 2/25/2005
Citation: Dong, F., Esberg, L.B., Roughead, Z.K., Ren, J., Saari, J.T. 2005. Increased contractility of cardiomyocytes from copper-deficient rats is associated with upregulation of cardiac insulin-like growth factor-I receptor. American Journal of Physiology Heart and Circulatory Physiology. 289:78-84.

Interpretive Summary: Hearts of animals subjected to severe dietary copper deficiency exhibit a variety of structural and functional defects that resemble heart failure. Paradoxically, when the function of individual heart cells from these animals is examined, they show an increased ability to contract. We noted in studies by others that, in hearts exhibiting failure from other causes, a transient increase in contractile ability accompanies the failure and that the cause of this increased contraction has often been related to an increase in a particular growth factor, termed insulin-like growth factor-I (IGF-I). We examined hearts of copper-deficient rats for changes in IGF-I, its genetic message and its receptor and found that, although IGF-I and its genetic message were reduced, the amount of IGF-I receptor was increased. This indicates an increase in sensitivity to IGF-I. Further, when the contractile ability of individual hearts cells was measured, the increase in contraction of copper-deficient cells was found to be blocked by an inhibitor of the IGF-I receptor. We conclude that the increase in ability of copper-deficient cells to contract is caused by an increase in sensitivity to IGF-I, an event that may act to compensate for and thus foreshadow heart failure. This study illustrates the importance of dietary copper to heart function by further delineating the mechanism of copper deficiency-induced heart failure.

Technical Abstract: Hearts from severely copper (Cu)-deficient rats show a variety of pathological defects, including hypertrophy and, in intact hearts, depression of contractile function. Paradoxically, isolated cardiomyocytes from these rats exhibit enhanced contractile properties. Because hypertrophy and enhanced contractility observed with other pathologies is associated with elevation of IGF-I, this mechanism was examined for the case of dietary Cu deficiency. Male, weanling Sprague-Dawley rats were provided diets that were deficient (~0.5 mg Cu/kg diet) or adequate (~6 mg Cu/kg diet) in Cu for five weeks. IGF-I was measured in serum and heart by an ELISA method, cardiac IGF-I and IGF-II receptors and IGFBP-3 were measured by Western blotting, and mRNAs for cardiac IGF-I and IGF-II were measured by RT-PCR. Contractility of isolated cardiomyocytes was assessed by a video-based edge-detection system. Cu deficiency depressed serum and heart IGF-I and heart IGFBP-3 protein levels and increased cardiac IGF-I receptor protein. Cardiac IGF-II protein and mRNA for cardiac IGF-I and IGF-II were unaffected by Cu deficiency. A Cu deficiency-induced increase in cardiomyocyte contractility, as indicated by increases in maximal velocities of shortening (-dL/dt) and re-lengthening (+dL/dt) and decrease in time to peak shortening (TPS), was confirmed. These changes were largely inhibited by use of H-1356, and IGF-I receptor blocker. We conclude that enhanced sensitivity to IGF-I, as indicated by an increase in IGF-I receptor protein, accounts for the increased contractility of Cu-deficient cardiomyocytes and may presage cardiac failure.