| This thesis documents characterization of mice (MHC-ODC mice) with cardiac specific expression of a stable ornithine decarboxylase (ODC), a rate-controlling enzyme in the biosynthesis of polyamines. The MHC-ODC mice exhibit increased arginase activity. Arginine is converted to ornithine by arginase, and serves as a common precursor for the nitric oxide (NO) pathway and the polyamine biosynthetic pathway. Therefore, our objectives involved characterization of the cardiac hypertrophy in the MHC-ODC mice and investigation of the interactions between polyamine and nitric oxide signalling of the MHC-ODC mice.; The specific aims designed to achieve these objectives of study determine the effect of increased ODC on the specific characteristics of cardiac hypertrophy such as cell size, collagen content, and protein synthesis in the heart, to determine the effect of overexpression of ODC and a constitutively active form of the alpha-1B adrenergic signalling receptor (CAM) in the heart tissue, to ascertain whether increased arginine alters NO signalling in the MHC-ODC mice and to determine if the inhibitory role of nitric oxide on the polyamines is important in the MHC-ODC mouse model.; Specific aim one revealed that increased ODC in cardiac tissue was sufficient to increase ventricular mass, myocyte size, collagen content and protein synthesis and to decrease blood pressure, heart rate, and stroke volume. Specific aim two demonstrated that constitutive adrenergic signalling in MHC-ODC results in symptoms of atrial thrombosis and fibrillation paired with congestion and hemorrhage of the lungs. A similar phenotype including atrial thrombosis and fibrillation paired with right ventricular dilation and death, independent of hypertrophy was described in specific aim three when MHC-ODC mice were treated with arginine in the presence of pharmacologically induced adrenergic signalling. Finally, specific aim four documented the ability of NO to inhibit ODC via S-nitrosylation in cultured cells and also illustrated increased peroxynitrite staining, indicative of high NO levels, in the cardiac tissue of the MHC-ODC mice. These observations, paired with the ability of nitric oxide synthase inhibition to increase survival of the arginine and isoproterenol-treated MHC-ODC mice, demonstrate cross talk between the polyamine and NO pathways in our in vivo model. |
