Abstract 160: Cardiomyocyte CaMKII Mediates Expression of Pro-inflammatory Chemokines and Cytokines, Macrophage Infiltration and Cardiac Remodeling in Response to Pressure Overload

Abstract

Background: There is evidence that inflammation is associated with pressure overload induced cardiac remodeling and heart failure, as well as evidence for a role of CaMKII in remodeling and heart failure development. Whether CaMKII mediates inflammatory responses that contribute to its role in adverse remodeling following TAC has not been established. Methods and Results: CaMKIIδ knockout (CKO) mice in which CaMKIIδ was selectively deleted from cardiomyocytes were subjected to pressure overload by transverse aortic constriction (TAC). By 3 days, the earliest time examined, there were marked increases in cardiac mRNA levels for pro-inflammatory chemokines CCL2 (MCP-1, ~15 fold), CCL3 (MIP1α, ~20 fold) and cytokines (IL-6, ~50 fold). These responses were markedly attenuated (by 56%, 43% and 42 % respectively) in the CKO mice. NFkB signaling was also increased in control heart at 3 days of TAC but not in CKO. Immunohistochemical analysis showed increases in CD68+ macrophage by 7 days TAC which further increased by 14days of TAC. Macrophages accumulation was also significantly attenuated in the CKO mice (50% decrease at 7day, 40% decrease at 14 days). Fibrosis was assessed by Masson trichrome staining and increases in collagen gene expression (col1a1 and col3a1 mRNA). Both were clearly elevated after 14 and 28 days TAC and significantly attenuated in the CKO mice. Conclusion: Our results indicate that activation of CaMKII localized in cardiomyocytes initiates an inflammatory transcriptional program within cardiomyocyte. We suggest that this drives immune cell recruitment and is in turn associated with development of fibrosis. Early inflammatory responses and their sequelae may thus be responsible for involvement of CaMKII in the progression from hypertrophy to heart failure.