|Wold, L - UNIV NORTH DAKOTA|
|Duan, J - UNIV NORTH DAKOTA|
|Ren, Jun - UNIV NORTH DAKOTA|
|Carlson, H - UNIV NORTH DAKOTA|
|Bode, Ann - HORMEL INST, UN MINNESOTA|
|Lentsch, A - UNIV CINCINNATI, OHIO|
|Schuschke, Dale - UNIV LOUISVILLE, KY|
Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 21, 2006
Publication Date: December 1, 2006
Repository URL: http://handle.nal.usda.gov/10113/46391
Citation: Saari, J.T., Wold, L.E., Duan, J., Ren, J., Carlson, H.L., Bode, A.M., Lentsch, A.B., Zeng, H., Schuschke, D.A. 2006. Cardiac nitric oxide synthases are elevated in dietary copper deficiency. Journal of Nutritional Biochemistry. doi:10.1016/j.jnutbio.2006.07.006. Interpretive Summary: Evidence is accumulating that dietary copper deficiency leads to symptoms that resemble heart failure. Although molecular events leading to failure have been determined for heart failure of other causes, evidence is sparse for that caused by copper deficiency. Nitric oxide is a molecule that appears to be central to both the failure process and survival mechanisms that are invoked when heart failure is imminent. Depending on its amount and source, nitric oxide can act as either a mediator of heart damage or as a protector of heart function. We have previously shown that nitric oxide production is elevated in copper-deficient hearts. To further characterize altered nitric oxide signaling in copper deficiency, we measured protein levels of two forms of an enzyme, nitric oxide synthase, that produce nitric oxide, the ability of those enzymes to produce nitric oxide, as well as a factor that genetically increases production of one of the enzymes. All were elevated, suggesting that nitric oxide is likely involved in the failure process and, perhaps, survival mechanisms in copper-deficient hearts. This research advances our understanding of how dietary copper contributes to heart health.
Technical Abstract: Dietary copper(Cu) deficiency leads to cardiac morphological and functional defects suggestive of heart failure. However, simultaneous cytoprotective events also appear to occur. The molecular mechanisms responsible for this complex alteration of cardiac function by Cu deficiency have not been elucidated. Because prior work has implicated altered nitric oxide (NO) metabolism in this altered function, we have examined this pathway in further detail. Male Sprague-Dawley rats were fed diets that were either Cu-adequate (6 mg Cu/kg diet) or Cu-deficient (<0.5 mg Cu/kg diet) for 5 weeks. Endothelial (eNOS) and inducible nitric oxide synthase (iNOS) protein expression, as measured by Western blot analysis, were 58% and 40% higher, respectively, in Cu-deficient than in Cu-adequate rat hearts. Cardiac NOS activity, as measured by conversion of 3H-arginine to 3H-citrulline, was 130% higher in Cu-deficient than in Cu-adequate rats. NFkB is a known transcription factor for iNOS. Activation of NFkB, determined by an ELISA for the p65 subunit, was found to be 33% higher in Cu-deficient than in Cu-adequate rats. Coupled with prior evidence of elevated cardiac nitrate/nitrite production in cu-deficient rats, these data suggest multiple pathways for enhanced NO production in Cu-deficient hearts and suggest possible mechanisms for altered cardiac function under dietary Cu deficiency.