Methyl metabolism in obesity-related cardiac remodeling

Cardiovascular disease (CVD) is the second leading cause of death in Canada. Obesity is a well-established risk factor for CVD and its prevalence has increased dramatically across the globe during recent decades. In the setting of obesity, excess lipid accumulation in the heart leads to changes in cardiac function and metabolism of CVD. The molecular mechanisms contributing to these obesity-related CVDs are not well understood, and may involve DNA methylation. Methylation of DNA is a post-replication modification that provides ‘marks’ in the genome, such that genes are set to be transcriptionally activated or silenced. DNA methyltransferases are responsible for the methylation of DNA and use S-adenosylmethionine (AdoMet) as the methyl donor. The metabolism of methyl groups and the production of AdoMet involve three interrelated pathways: folate cycle, methionine cycle, and transsulfuration pathway. As such, disturbances in methyl metabolism could change DNA methylation patterns in the heart and be involved in the pathogenesis of CVD. The objective of this thesis was to test the general hypothesis that disturbances in methyl metabolism contributes to obesity-related cardiovascular pathology. C57BL/6J mice with (+/-) and without (+/+) a heterozygous targeted disruption of the gene for cystathionine-beta-synthase (CBS), an enzyme required for the transsulfuration pathway, were used to disrupt methyl metabolism. At weaning, mice were fed either a control diet or a high-fat diet (HFD, 60% energy from fat) to induce excess adiposity (obesity). Studies in the thesis revealed three major findings. First, disturbances in methyl metabolism enhanced cardiac lipotoxicity associated with diet-induced obesity. Second,disturbances in methyl metabolism altered cardiac energy metabolism and function associated with obesity-related cardiac remodeling. Third, disturbances in methyl metabolism contributed to a tissue-specific relationship between ‘methylation capacity’ (AdoMet/AdoHcy ratio), DNA methylation, and gene expression in Cbs +/- mice. In summary, these data revealed a unique role for CBS in cardiac fatty acid metabolism, possibly contributing to the pathology of obesity-related cardiac remodeling. These findings also provide first time evidence of disturbances in methyl metabolism and the functional consequences as it pertains to DNA methylation, regulation of gene expression, and cardiac remodeling in mice with diet-induced obesity.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat