Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca ²⁺ /Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling

Abstract

Background: Inflammation is associated with cardiac remodeling and heart failure, but how it is initiated in response to non-ischemic interventions in the absence of cell death is not known. We tested the hypothesis that activation of CaMKIIδ in cardiomyocytes in response to pressure overload elicits inflammatory responses leading to adverse remodeling. Methods: Mice in which CaMKIIδ was selectively deleted from cardiomyocytes (CMs) (Cardiac specific knockout; CKO) and floxed control (CTL) mice were subjected to transverse aortic constriction (TAC). The effects of CM-specific CaMKIIδ deletion on inflammatory gene expression, inflammasome activation, macrophage accumulation and fibrosis were assessed by qPCR and histochemistry and ventricular remodeling by echocardiography. Results: TAC induced increases in cardiac mRNA levels for pro-inflammatory chemokines and cytokines within 3 days and these responses were significantly blunted when cardiomyocyte CaMKIIδ was deleted. Apoptotic and necrotic cell death were absent at this time. CMs isolated from TAC hearts mirrored these robust increases in gene expression which were markedly attenuated in CKO. Priming and activation of the NLRP3 inflammasome, assessed by measuring IL-1β and NLRP3 mRNA levels, caspase-1 activity and IL-18 cleavage, were increased at day 3 post-TAC in CTL hearts and in CMs isolated from these hearts. These responses were dependent on CaMKIIδ and associated with activation of NFkB and ROS. Accumulation of macrophages observed at day 7–14 post-TAC was diminished in CKO and by blocking MCP-1 signaling, deletion of CM MCP-1 or inhibition of inflammasome activation. Fibrosis was also attenuated by these interventions and in the CKO heart. Ventricular dilation and contractile dysfunction observed at day 42 post-TAC were diminished in the CKO. Inhibition of CaMKII, NFkB, inflammasome or MCP-1 signaling in the first one or two weeks after TAC decreased remodeling but inhibition of CaMKII after two weeks did not. Conclusions: Activation of CaMKIIδ in response to pressure overload triggers inflammatory gene expression and activation of the NLRP3 inflammasome in CMs. These responses provide signals for macrophage recruitment, fibrosis and myocardial dysfunction in the heart. Our work suggests the importance of targeting early inflammatory responses induced by cardiomyocyte CaMKIIδ signaling to prevent progression to heart failure.

Ethanol-activated CaMKII signaling induces neuronal apoptosis through Drp1-mediated excessive mitochondrial fission and JNK1-dependent NLRP3 inflammasome activation.

“…Previous studies have shown that CaMKII activated Drp1 via phosphorylation at Ser 616 and an increase in Drp1 translocation to the mitochondria induced excessive mitochondrial fragmentation [53,54]. Our data showed that CaMKII activated by ethanol- Many studies have reported that an increase in intracellular calcium induces inflammasome formation and CaMKII signaling triggers inflammasome activation in cardiomyocytes [55][56][57]. These results suggest that CaMKII signaling is important for inflammasome activation.…”

Autophagy and cardiac aging

“…The role of the NLRP3 inflammasome in cardiac diseases has been increasing recognized [113][114][115] and recent evidence further suggests that NLRP3 inflammasome activation occurs in cardiomyocytes within the heart [113,116,117]. For instance, our recent studies have shown that the NLRP3 inflammasome is activated in cardiomyocytes in response to angiotensin-II or pressure overload and that this contributes to recruitment of immune cells, cardiac fibrosis, and ventricular dysfunction [116,118]. Involvement of inflammasome signaling in cardiac disease has also been suggested by clinical findings using interventions that inhibit IL-1β function or block the IL-1 receptor [119,120].…”

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation

“…Recently, accumulating evidence has suggested that the NLRP3 inflammasome, composed of apoptosis‐associated speck‐like protein containing a CARD (ASC), caspase‐1 and NLRP3, has been recognized as an important mediator of the inflammatory response (Franchi, Eigenbrod, Muñoz‐Planillo, & Nuñez, 2009; Sutterwala et al., 2006). Notably, activation of the NLRP3 inflammasome participates in several cardiovascular‐related inflammatory process (Abderrazak et al., 2015; Gan et al, 2017; Suetomi et al., 2018). Activation of the NLRP3 inflammasome requires NF‐κB signalling (Bauernfeind et al., 2009).…”