Abstract 689: Cystathionine-Beta-Synthase Deficiency Induces Cardiac Hypertrophy and Contributes to Diminished Fatty Acid Oxidation in Mice with Diet-Induced Obesity

Obesity-related cardiac lipid accumulation is associated with lipotoxicity and dysfunction. Cysteine is required for the synthesis of the antioxidant glutathione, which can be supplied by the transsulfuration of homocysteine by cystathionine-beta-synthase (Cbs). Cbs+/- mice with diet-induced obesity had greater glucose intolerance and lipotoxicity in the heart. Our objective was to determine the functional effects and mechanisms of cardiac lipotoxicity in Cbs+/- mice with diet-induced obesity. Cbs+/- and Cbs+/+ mice were fed a control diet or a high-fat diet (HFD) from weaning for 20 weeks. As expected, Cbs+/+ and Cbs+/- mice fed the HFD had greater final body weights, visceral (retroperitoneal and epididymal) and subcutaneous (inguinal) adiposity compared to mice fed the control diet. Cbs+/- mice had greater heart weights accompanied by higher concentrations of long chain polyunsaturated fatty acids arachidonic acid, 20:4n6 (AA) and docosahexaenoic acid, 22:6n3 (DHA) in the heart compared to Cbs+/+ mice. Mice fed the HFD had higher AA, but lower DHA concentrations in the heart compared to mice fed the control diet, with the greatest effect in Cbs+/- mice. Isolated working hearts revealed a reduced heart rate and cardiac output in Cbs+/- mice fed the control diet compared to Cbs+/+ mice. Independent of diet, Cbs+/- mice also had reduced aortic flow compared to Cbs+/+ mice, with a higher coronary flow only in Cbs+/- mice fed the HFD. Working hearts also revealed that Cbs+/- mice had lower palmitate oxidation rates compared to Cbs+/+ mice, with higher palmitate oxidation and glycolysis rates in mice fed the HFD compared to mice fed the control diet. Cbs+/- mice had a lower ratio of phosphorylated-AMP activated protein kinase alpha (AMPKα)/AMPKα expression (regulator of cellular energy) in heart compared to Cbs+/+ mice, and this occurred to a greater extent in those fed the HFD. Furthermore, we observed a higher ratio of collagen type 1(COL1α1)/ collagen type 3 (COL3α1) expression (implicated in myocardial stiffness) in heart, only in Cbs+/- mice fed the HFD. Collectively, these findings suggest that cardiac lipotoxicity in Cbs+/- mice with obesity is associated with cardiac hypertrophy, impaired cardiac fatty acid metabolism, and cardiac dysfunction.