Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Epstein, Paul N.
Increased glycolysis; Heart failure; Decreased glycolysis; Oxidized mitochondrial DNA; Fructose-2; 6-bisphosphate; 8-oxoguanine DNA glycosylase 1
Myocardial infarction; Glucose--Metabolism; Mitochondrial DNA
Heart failure is a leading cause of morbidity and mortality in the USA. During the development of heart failure, many cardiac parameters change at the same time including fuel metabolism, oxidative stress and mitochondrial function. Each of these changes occurs in the context of multiple other abnormalities in the failing heart. This complexity makes it difficult to discern the importance of each of these parameters. In this dissertation changes in glucose metabolism and mitochondrial DNA repair have been targeted separately and specifically in the heart to test their roles in heart failure independently. Abnormal glucose metabolism is always found in heart failure patients. During heart failure there is a significant increase in cardiac glycolysis. On the other hand, diabetic patients, who are at increased risk of heart failure show the opposite change in glucose metabolism, their level of glycolysis goes down. In these studies separate lines of transgenic mice with increased or decreased glycolysis were used to test if these changes in glucose metabolism altered the development of heart failure induced by pressure overload after transaortic constriction (TAC) surgery. Cardiac glycolysis was targeted by 2 transgenes that alter the level of fructose-2 ,6-P2 (F-2,6-P2), which activates phosphofrucokinase. The Mb trans gene reduces F-2,6-P2 and slows glycolysis. The Mk transgene increases F-2,6-P2 and speeds glycolysis. Mb and Mk transgenic hearts had normal structure and function after sham surgery but they were both much more susceptible to damage from T AC surgery than non-transgenic mice. In both lines of mice TAC produced more fibrosis, more collagen expression, greater hypertrophy, lower fractional shortening, higher lung weight and reduced energy reserves. Mb mice also showed more oxidative stress. These results indicate loss of cardiac flexibility to control glucose metabolism is detrimental to the heart. Cardiac failure is associated with increased levels of oxidized mitochondrial DNA (mtDNA). It is not known if oxidized mtDNA contributes to cardiac dysfunction. To test if protection of mtDNA can reduce cardiac injury, we produced transgenic mice with cardiomyocyte-specific overexpression of the mitochondrial form of the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG 1). OGG 1 transgenic mice demonstrated significantly lower cardiac mitochondrial levels of the DNA guanine oxidation product 7,8-dihydro-8-oxoguanine (8-oxo-dG). This was true under basal conditions, after Doxorubicin administration or after TAC. OGG 1 mice were tested for protection from TAC surgery. Compared to FVB-TAC mice, hearts from OGG 1-TAC mice had lower levels of ß-MHC mRNA but they did not display significant differences in hypertrophy or function. The principle benefit of OGG 1 overexpression was a significant decrease in T AC induced cardiac fibrosis, indicated by reduced Sirius Red staining and by significantly decreased induction of collagen 1 and 3 mRNA expression. These results provide a new model to assess the cardiac effects of mtDNA damage and demonstrate that oxidation of mtDNA contributes to cardiac pathology.
Wang, Jianxun 1969-, "Cardiac abnormalities after transaortic constriction are worsened by changing glucose metabolism and benefited by repair of mitochondrial DNA." (2011). Electronic Theses and Dissertations. Paper 1517.