Abstract 228: CaMKII as a Link Between Inflammation and Fibrosis Induced by Chronic Isoproterenol and Angiotensin II Treatment
The Ca2+/calmodulin-dependent kinase, CaMKIIδ, is an established mediator of the development of heart failure and myocardial injury. Cardiac inflammation has been increasingly recognized as an important player in these cardiac pathophysiological changes. We previously demonstrated that CaMKIIδ contributes to cardiac inflammation induced by ischemia/reperfusion through activation of cardiomyocyte NF-kB. In the current study we ask whether angiotensin II (Ang II) and isoproterenol (ISO), both known to activate CaMKII, promote cardiac inflammation through this protein kinase and its effects on NF-kB activation. In addition, chronic ISO and Ang II treatment promote cardiac fibrosis and we hypothesize that this response is initiated through activation of CaMKIIδ and subsequent inflammatory responses. We report on our recent findings that show attenuated inflammatory cytokine expression (e.g. IL-6, MCP1, and TNFα) in response to 7 days Ang II infusion in mice in which CaMKIIδ is specifically deleted in cardiomyocytes (cardiac specific knockout; CKO). In addition the expression of fibrotic markers (e.g. col1a1, col3a1, and CTGF) in response to Ang II infusion is decreased in the CKO mice. This is associated with attenuated fibrosis as evident in histological analysis of CKO vs WT heart sections. Ongoing studies will compare the effects of chronic ISO and Ang II in CKO and WT mice to determine whether inflammation precedes fibrosis and assess the extent to which apoptosis induced by CaMKII activation plays a part in these responses. Currently, we are determining whether Ang II and ISO act through CaMKII to activate NF-kB in the cardiomyocyte compartment to induce proinflammatory and profibrotic factors and whether preventing the expression of these factors block development of further inflammatory and fibrotic responses. Findings from these studies may implicate CaMKII as a promising therapeutic target for attenuating cardiac fibrosis.
Author Disclosures: A. Willeford: None. J. Heller Brown: None.
- © 2015 by American Heart Association, Inc.