Diabetes is associated with both coronary vascular disease and cardiac ischemia resulting in accelerated and aggressive cardiac disease. In the previous 3 years we have focused on the potential role of reduced NO production on the diabetic heart. We have found that alloxane induced type I diabetes is characterized by increased mRNA for eNOS but reduced protein and NO production. We have also shown that there are marked shifts in cardiac substrate use, consistent with the role of NO in the control of cardiac fatty acid and glucose uptake. We have also found that the decrease in NO production results in altered regulation of myocardial oxygen consumption by NO perhaps contributing to a mismatch between oxygen delivery and demand. In the current application we will continue to focus on the role of NO in the control of cardiac function and metabolism.
In specific aim 1, we will examine the potential that phosphorylation can increase the activity of eNOS and compensate for the reduction in eNOS protein which we observed in the diabetic heart. In vitro studies will be used to sort out the signaling mechanism and the Bezold-Jarisch reflex coronary dilation will be used as method to study this in vivo. Previously we have found that diabetes shifts substrate uptake in the heart from fatty acids to keto acids with no glucose uptake despite the marked increase in plasma glucose. We have also found that these shifts occur at about the time that NO production by the heart falls. We will investigate the relationship between NO production and substrate use in the diabetic heart in specific aim 2 of this proposal. Whereas most of our studies have focused on type 1 diabetes, the incidence of type II diabetes is increasing in the population at epidemic rates. To investigate the role of altered NO production and the mechanism responsible we have begun studies in the Zucker fatty rat (Type II) and to contrast those findings with rats treated with Streptozotocin (Type I) or alloxan. Interestingly, and the focus of specific aim 3 we have found that eNOS protein is normal in the heart of the Zucker rat accompanied by a reduction in NO bioactivity (unlike the Strep treated rat where eNOS protein is reduced by 50%). These data imply an important role for superoxide anion in Type II diabetes and will be the focus of this specific aim.
In specific aim 4 we will determine whether treatment of the diabetic dog heart with growth factors to recruit cardiac stem cells results in alterations in cardiac function after infarction. Because diabetes is characterized by aggressive myocardial ischemia we postulate that in the diabetic heart compensatory mechanisms such as stem cell recruitment are deficient resulting in exaggerated ischemia. Thus this proposal will continue work on the role of NO in the control of cardiac function and metabolism and extend these studies to the role of cardiac stem cells in the genesis and treatment of the diabetic ischemic heart.
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