The Role of CaMKII delta in Pathophysiological Responses Induced by Beta-Adrenergic Receptor Stimulation and Angiotensin II

The initial studies of my graduate research, which resulted in a co-authorship and for clarity reasons is presented in this dissertation in full, utilized calcium/calmodulin-dependent protein kinase II (CaMKII) global knockout mice to determine the requirement for the kinase in cardiac remodeling and heart failure induced by chronic beta-adrenergic receptor (beta-AR) stimulation. Specifically, my work focused on the requirement of CaMKII in hypertrophic and fibrotic responses induced by chronic treatment with the -adrenergic receptor agonist isoproterenol (ISO). We found that hypertrophy induced by daily ISO injection or infusion for up to 4 weeks was preserved in animals lacking CaMKII. In contrast, fibrotic responses induced by the same dosing regimen were attenuated by CaMKII gene deletion.The primary work in my dissertation utilized a cardiomyocyte-specific CaMKII knockout mouse model to study the role of cardiomyocyte CaMKII in inflammatory and fibrotic responses induced by angiotensin III (Ang II). We hypothesized that CaMKII initiates inflammatory gene expression and inflammatory cell recruitment and leads to cardiac fibrosis. Knockout mice in which CaMKII is specifically deleted in cardiomyocytes showed attenuated inflammatory gene expression induced by 1-day Ang II infusion as compared to control (CaMKIIfl/fl) mice. These responses were dissociated from cell death and differences in blood pressure. Monocyte chemotactic protein 1 (MCP-1) was induced in cardiomyocytes in response to Ang II and this response was found to be dependent on CaMKII. Macrophage recruitment induced by 1-day Ang II infusion was also found to be dependent on CaMKII signaling in the cardiomyocyte. Ang II infusion primed and activated the inflammasome and expression of CaMKII in cardiomyocytes in vitro also primed and activated the inflammasome through a reactive oxygen species-dependent pathway. Pharmacological inhibition of either the receptor to MCP-1 or the inflammasome attenuated Ang II-induced inflammatory responses. Longer term Ang II infusion elicited robust fibrosis and this response was attenuated in mice lacking CaMKII in the cardiomyocyte or treated with either inhibitor. These results demonstrate a critical role for a cardiomyocyte autonomous transcriptional pathway, triggered by CaMKII in the cardiomyocyte, in inflammatory responses induced by Ang II and leading to fibrosis