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CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis
Andrew Willeford, … , Shigeki Miyamoto, Joan Heller Brown
Andrew Willeford, … , Shigeki Miyamoto, Joan Heller Brown
Published June 21, 2018
Citation Information: JCI Insight. 2018;3(12):e97054. https://doi.org/10.1172/jci.insight.97054.
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Research Article Cardiology Inflammation

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

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Abstract

Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II–induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.

Authors

Andrew Willeford, Takeshi Suetomi, Audrey Nickle, Hal M. Hoffman, Shigeki Miyamoto, Joan Heller Brown

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Figure 1

Deletion of CaMKIIδ in the cardiomyocyte attenuates Ang II–induced inflammatory gene expression in the heart and monocyte chemotactic protein 1 expression in the myocyte.

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Deletion of CaMKIIδ in the cardiomyocyte attenuates Ang II–induced infla...
(A) mRNA expression of monocyte chemoattractant protein 1 (Ccl2/MCP1), macrophage inflammatory protein 1α (Ccl3/MIP1α), CXC motif ligand 1 (Cxcl1), CXC motif ligand 2 (Cxcl2),IL-1β (Il1b), and IL-6 (Il6) in ventricular lysates of Camk2dfl/fl control (CTL) and cardiomyocyte-specific CaMKIIδ KO (CKO) mice infused with saline (vehicle [Veh]) or Ang II (1.5 μg/kg/min) for 1 day as measured by qPCR (n = 6–9/group). (B) Ccl2/MCP1 mRNA expression in adult mouse ventricular myocytes isolated from control and CKO mice after 1-day saline or Ang II infusion as measured by qPCR. Hearts were enzymatically digested, and resultant cell suspension was allowed to sediment by gravity. Supernatant was aspirated and pellet washed 2 times before being processed for RNA extraction, cDNA synthesis, and qPCR (n = 3/group). (C) Western blot and quantitation of MCP1 protein in ventricular lysates of control and CKO mice at 1 day of Ang II infusion. GAPDH, loading control (n = 4/group). Two-way ANOVA was used for all comparisons. *P < 0.05 vs. Veh; **P < 0.01 vs. Veh; #P < 0.05 CTL Ang II vs. CKO Ang II.

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