Calcium/Calmodulin‐dependent Protein Kinase II (CaMKII) Signaling in Cardiomyocytes Initiates Inflammatory Responses Required for Adverse Cardiac Remodeling in Response to Pressure Overload.
Authors: Suetomi Takeshi , Willeford Andrew , Li Michelle , Miyamoto Shigeki , Brown Joan Heller 
Published: June 2021

Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to non‐ischemic interventions i.e. in the absence of cell death is not known. We tested the hypothesis that the activation of CaMKII in cardiomyocytes stimulates inflammatory gene expression and subsequent responses leading to adverse remodeling following transverse aortic constriction (TAC). Mice in which CaMKIIdelta was selectively deleted from cardiomyocytes (Cardiac specific knockout; CKO) and floxed control (CTL) mice were subjected to pressure overload by TAC. Significant increases in CaMKII activity and NFkB activation were observed in CTL but not in CKO hearts at 1.5 days of TAC. Cardiac mRNA levels for pro‐inflammatory chemokines and cytokines increased by 1.5 days and peaked at 3 days with 5–20 fold increases vs sham in MCP‐1, MIP1alpha, and IL‐6. These responses were significantly decreased in the CKO mice. Cardiomyocytes isolated from CTL and CKO mice following TAC showed similar increases in gene expression and attenuation of 60 to 70% when CaMKII was deleted. Priming and activation of inflammasomes was assessed by measuring NLRP3 mRNA levels and caspase 1 activity at 3 days of TAC. Both were significantly increased in CTL but not in CKO hearts and isolated cardiomyocytes. Immunohistochemical analysis revealed significant CD68+ macrophage accumulation by 7 and 14 days of TAC which was significantly attenuated in the CKO mice. Fibrosis assessed by Masson‐trichrome staining, collagen (col1a1, col3a1) and periostin mRNA expressions occurred slightly later and was also significantly attenuated in the CKO mice. Cardiac echocardiography revealed severe ventricular dilation and decreased ejection fraction at 42 days of TAC, both of which was diminished in the CKO vs CTL. Pharmacologic NLRP3 blockade between days 1–7 after TAC significantly reduced caspase 1 activation, CD68 positive cell accumulation, fibrosis and attenuated loss of contractile function at 42 days of TAC implicating inflammasome activation as an early event in remodeling. Our findings demonstrate that cardiomyocytes are a site at which inflammatory transcriptional programs and inflammasome activation are initiated through CaMKII. The functional significance of this response in driving subsequent immune cell recruitment, fibrosis and adverse remodeling is suggested by our studies using CaMKII deletion and is being further investigated through pharmacologic and genetic blockade. Our work may establish the critical importance of early inflammatory responses to cardiomyocyte CaMKII signaling as targets to prevent progression from hypertrophy to heart failure.Support or Funding InformationFirst Author (Takeshi Suetomi) is supported by the Uehara memorial foundation (Japan) and the American Heart Association Postdoctoral Fellowship (17POST33680017).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.