Project Number: 5450-51000-038-00
Project Type: Appropriated

Start Date: Jul 21, 2004
End Date: Apr 30, 2009

Objective:
Overall, to determine, using animal models, whether copper (Cu) intakes consistent with those observed in humans can adequately support cardiovascular functions. To develop a strategy for assessment of marginal copper deficiency in animals; to use this strategy to determine biomarkers of copper status that are suitable for assessment of marginal status in humans. To determine the contribution of oxygen- and nitrogen-derived reactive species to the cardiomyopathy (metabolic, contractile) induced by Cu deficiency, and the dietary intakes at which this pathology occurs. To determine whether low Cu intakes consistent with those observed in humans can impair nitric oxide-dependent control of blood vessels and blood pressure regulation. To determine whether the oxidative stress induced by Cu deficiency affects homocysteine metabolism and, thereby, cardiovascular function, and whether such effects influence nitric oxide-dependent signal transduction and/or other mechanisms that affect atherosclerosis. To determine whether marginal Zn deficiency can exacerbate or unmask cardiovascular effects of sub-optimal Cu status by virtue of its role in oxidative/nitrosative metabolism.

Approach:
Laboratory animals of varying ages and, in some cases, varying genetic makeup will be fed diets containing copper in severely deficient, marginally deficient or adequate amounts for varying periods of time. Based on comparisons to reliable invasive markers of copper status, non-invasive biomarkers will be tested for validity in assessing marginal copper deficiency. Tests of cardiovascular function and examinations of mechanism of depressed function will be made over ranges of copper status varying from severely-deficient to adequate. Cardiovascular functional measurements include heart contractile function, cardiac mitochondrial respiration and respiratory complex activity, blood vessel contractility and blood pressure. Atherosclerosis will be assessed by microscopic observation of blood vessels. Examination of mechanisms of depressed function will focus on the effects of oxidative stress and altered nitric oxide metabolism known to occur in copper deficiency. Such examination will include assessment of oxidative/nitrosative damage, altered nitric oxide signaling and altered homocysteine metabolism and will extend to measurement of transcription factors, mRNA and enzymes that influence and are influenced by oxidative stress and nitric oxide signaling.