Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Epstein, Paul N.
Diabetes--Complications; Heart--Diseases; Coronary heart disease
Diabetic cardiomyopathy (DCM) is a common complication leading to accelerated cardiovascular failure in diabetic patients. Even though the exact mechanism(s) behind this disease still remain unclear, research from several laboratories including our own suggests that reactive oxygen species (ROS) play a very important role in the development of DCM. In our lab, we have developed and characterized a diabetic transgenic mice line, designated OVE26, which clearly develops diabetic cardiomyopathy. Comparison of protein expression patterns in the hearts of 120-day-old control and diabetic mice reveals 22 proteins that are differentially expressed in OVE26 mice hearts, most of which are involved in energy metabolism. Surprisingly, 10 of 20 proteins that are identified by mass spectrometry are located in mitochondria, suggesting mitochondria as a critical target for ROS damage. The finding of the up-regulation of all 10 proteins also corresponds well with the concept that moderate oxidative stress can stimulate mitochondrial biosynthesis to compensate for the impaired cell functions. Study on mitochondrial morphology also shows abnormal cardiac structure and damage, further pointing to mitochondria as one of the major sites of ROS attack in diabetic cardiomyopathy. In an effort to prevent the mitochondrial damage we saw in diabetic hearts, we have developed transgenic lines that overexpress the main mitochondrial antioxidant protein, MnSOD specifically in cardiomyocytes. Preliminary data from the transgenic mice that overexpress MnSOD in diabetic heart showed that this antioxidant enzyme was effective in protecting the morphology of the diabetic heart. Our proteomic and morphologic analyses indicate that mitochondria are an important target of diabetic cardiomyopathy. Protection by overexpression of mitochondrial MnSOD indicates that ROS are involved in this damage.
Shen, Xia 1976-, "Proteomics and morphology demonstrate mitochondrial changes in diabetic cardiomyopathy." (2002). Electronic Theses and Dissertations. Paper 1316.