Abstract 13081: The Central Nervous System Regulates Inflammation and Cardiac Remodeling During Pressure Overload Through NLRP3 Inflammasome Activation

Background: Interleukin-1β (IL-1β) has been shown to be upregulated in the heart during pressure overload through Toll-like receptor (TLR) signaling and contribute to cardiac remodeling. IL-1β requires the proteolysis of pro-IL-1β in generation of active form, and the NLRP3 inflammasome has been reported to play a pivotal role in this process by the catalytic activation of caspase-1. This study was performed to clarify the role and the mechanisms of the NLRP3 inflammasome activation in pressure overload-induced cardiac hypertrophy. Methods and Results: Pressure overload was induced in mice by transverse aortic constriction (TAC). In wild-type (WT) mice, NLRP3 was upregulated in the heart after TAC with increased caspase-1 activation and active IL-1β production, which were suppressed in Nlrp3 knockout (KO) mice. At 2 weeks after TAC, KO mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function compared with WT mice, indicating impaired cardiac adaptive response to pressure overload. In vitro experiments revealed that extracellular ATP, in combination with a specific ligand for TLR2, synergistically induces cardiomyocyte hypertrophy and proliferation of fibroblasts and vascular endothelial cells through NLRP3 inflammasome activation via the P2X7 receptor. Pharmacological inhibition of the P2X7 receptor or depletion of extracellular ATP in WT mice resulted in suppressed NLRP3 inflammasome activation and impaired adaptive cardiac hypertrophy after TAC. ATP is one of neurotransmitters released from the sympathetic nerve terminals. We found that sympathetic activation induces caspase-1 activation in WT hearts, whereas sympathetic inhibition by the left stellate ganglionectomy or clonidine suppressed NLRP3 inflammasome activation and impaired adaptive cardiac hypertrophy after TAC in WT mice. Besides, WT mice undergoing ablation of afferent nerves from the heart by capsaicin showed the same phenotype with those with sympathetic inhibition after TAC. Conclusions: Our results suggest that NLRP3 inflammasome activation is regulated by the central nervous system through the ATP/P2X7 signaling axis and contributes to adaptive cardiac hypertrophy during pressure overload.