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Introduction:There is evidence that inflammation is associated with pressure overload induced cardiac remodeling and heart failure, as well as evidence for a role of Ca2+/ Calmodulin-dependent protein kinase II (CaMKII) in remodeling and heart failure development. Pressure overload triggers inflammatory gene expression and the activation of the NOD-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome in cardiomyocytes. These responses provide signals for macrophage recruitment, fibrosis, and myocardial dysfunction in the heart. However, the downstream mechanism is not elucidated.Methods and Results:Macrophage specific CaMKIIdelta knockout (mKO) mice were subjected to transverse aortic constriction (TAC). Cardiomyocyte mRNA levels for pro-inflammatory chemokines and cytokines increased and peaked with 5 to 10 folds vs sham in both control and mKO mice. Priming and activation of the NLRP3 inflammasome, assessed by measuring NLRP3 mRNA and caspase-1 activity, were increased by TAC in isolated cardiomyocytes of both control and mKO. In contrast, caspase-1 activation in isolated macrophage were attenuated in mKO. CD68 positive cell accumulation and cardiac fibrosis in cardiac tissue in response to pressure overload were also attenuated in mKO vs control (CD68 41 ± 9 cells/mm2vs 78 ± 13 cells/mm2, fibrotic area 8.5 ± 1.2 % vs 4.1 ± 0.9 %). Subsequent cardiac dysfunction in response to pressure overload were less impaired in the mKO vs control (ejection fraction 44 ± 3% vs 35 ± 6%).Conclusions:Activated CaMKIIdelta in response to pressure overload triggers inflammatory signals including NLRP3 inflammasome cascade in cardiomyocytes. It also contributes amplification of inflammasome signal in macrophages leading fibrosis and consequent cardiac dysfunction. CaMKIIdelta in cardiomyocytes and macrophages could be a therapeutic anti-inflammatory and anti-fibrotic target for preventing adverse cardiac remodeling and heart failure.