| Heart failure, the heart's inability to sufficiently deliver blood to meet the body's demand, is a leading cause of death in the U.S. As an adaptive response to stress, the heart undergoes structural remodeling resulting in enlargement known as cardiac hypertrophy. Although initially compensatory, chronic hypertrophy can lead to reduced contractility, often resulting in heart failure. The signaling mechanisms by which chronic hypertrophy transitions to heart failure are not well understood and are of great significance to advancing clinical treatment of heart failure. In cardiomyocytes, Ca 2+ is a critical second messenger involved in many cardiac signaling pathways, and changes in Ca2+ handling are associated with hypertrophy and dysfunction leading to heart failure. Several proteins are involved in intracellular Ca2+ regulation, one being Ca 2+/calmodulin-dependent protein kinase II, (CaMKII). This Ca 2+-sensitive protein kinase, which phosphorylates a number of known substrates, has emerged as a key molecule in hypertrophy and heart failure. CaMKII activity and expression are altered in heart failure patients and animal models of hypertrophy and heart failure. The predominant cardiac isoform is CaMKIIdelta, and two splice variants (subtypes), deltaB and delta C, differing only by a nuclear localization sequence, are present in the heart. Our lab has shown that overexpression of either subtype results in cardiac dysfunction, however whether the subtypes have differential roles is unclear. Studies presented in the first part of this dissertation extensively characterize the localization and activation of deltaB vs. delta C, and reveal that subtype localization is nonspecific, and enzyme localization governs its activation and function. CaMKIIdelta null mice overexpressing individual subtypes were generated and used throughout our studies to not only understand enzyme localization and activation, but also to provide an important perspective on whether deltaBB and deltaC have differential roles. The second part provides an in-depth study of the mechanism by which CaMKII deltaC contributes to heart failure, studied by crossing deltaC transgenic mice with several genetically altered mouse models in an effort to rescue the heart failure phenotype. While attenuation of the heart failure phenotype was not achieved, our findings provide insight into the maladaptive mechanisms that contribute to cardiomyopathy, and underscore the multidimensional role of CaMKII in the heart. |
