It is now known that the development of cardiovascular disease is attributed to an adverse combination of genetic and environmental risk factors. Those subjects presenting with the greatest number of risk factors develop a disease of the cardiovascular system at an earlier age. One genetic risk factor associated with cardiovascular disease is diabetes mellitus. Cardiovascular disease represents the most frequent cause of death in both Type 1 and Type 2 diabetes, and diabetics have a high incidence of atherosclerosis and ventricular dysfunction (i.e., diabetic cardiomyopathy). Previous studies have shown that diabetic myocardium exclusively relies on the metabolism of fatty acids for its metabolic needs. Evidence suggests that the abnormal storage of lipids, which is a result of increased fatty acid uptake by diabetic myocardium, leads to myocyte apoptosis. However, the biochemical link between myocardial lipid accretion, apoptosis, and cardiomyopathy is currently not known. The goal of this research project is to prepare radiotracers that can be used with the functional imaging technique, Positron Emission Tomography (PET), to study the molecular mechanisms that underlie cardiovascular disease associated with diabetes mellitus. Our working hypothesis is that increased lipid accretion in diabetic myocardium is caused by the abnormal expression of the nuclear hormone receptor transcription factors that are responsible for regulating fatty acid (FA) metabolism and lipid storage. Therefore, the first specific aim of this project is to develop PET-based radiotracers that can measure the functional activity of the two nuclear hormone transcription factors, PPARalpha and PPARgamma, which regulate these biochemical processes in normal and diabetic myocardium. The lead compounds for PET radiotracer development are a series of antidiabetic drugs, the fibrates and the glitazones, which reduce plasma lipid levels by acting as agonists of either PPARalpha or PPARgamma. A second goal of this project is to develop radiotracers that can be used to study the molecular mechanisms responsible for the lipotoxicity associated with diabetes. Our working hypothesis is that increased lipid accretion leads to the generation of reactive oxygen and nitrogen species (ROS/RNS) through the activation of inducible nitric oxide synthase (iNOS). The generation of ROS/RNS results in the nitration of proteins required for normal cellular function, and the disruption of this function leads to apoptosis and necrosis. Therefore, PET radiotracers will be developed in order to study the relationship between abnormal FA metabolism, iNOS induction, apoptosis (by imaging the enzyme, caspase-3), and necrosis (by imaging the enzyme, PARP-1). The use of these radiotracers to determine the role of iNOS, apoptosis and necrosis in cardiovascular disease will be initially studied in rodent models of diabetes. Finally, toxicity studies will be conducted on radiotracers developed by Project 1, and validated in rodent models of diabetes, in order to enable the clinical translation of this research to include imaging studies in Type 1 and Type 2 diabetics.
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