Submitted on October 26, 2004
Accepted on February 18, 2005
Increased contractility of cardiomyocytes from copper-deficient rats is associated with up-regulation of the cardiac insulin-like growth factor-I receptor
Feng Dong1, Lucy B Esberg2, Zamzam K Roughead3, Jun Ren4, and Jack T Saari3*
1 University of Wyoming, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, Laramie, WY, USA
2 University of North Dakota, Department of Pharmacology, Physiology and Therapeutics, School of Medicine, Grand Forks, ND, USA
3 U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND, USA
4 University of Wyoming, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, Laramie, WY, USA; University of North Dakota, Department of Pharmacology, Physiology and Therapeutics, School of Medicine, Grand Forks, ND, USA
* To whom correspondence should be addressed. E-mail: jsaari{at}gfhnrc.ars.usda.gov.
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 are 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 mRNAs 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, an 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.
