Abstract 15017: NLRP3 Inflammasome Activation Through the Heart-Brain Interaction Contributes to Adaptive Cardiac Hypertrophy in Response to Pressure Overload
Background: We have shown that interleukin-1β (IL-1β) upregulation via activation of Toll-like receptor 2 signaling contributes to adaptive cardiac hypertrophy in response to pressure overload. IL-1β requires the proteolysis of pro-IL-1β in generation of active form, and it has been reported that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome plays an important role in this process by the catalytic activation of caspase-1. This study was performed to clarify the role and the mechanisms of NLRP3 inflammasome activation in pressure overload-induced cardiac hypertrophy.
Methods and Results: At 2 weeks after transverse aortic constriction (TAC), Nlrp3 knockout (KO) mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function compared with wild-type (WT) mice (n=10), indicating impaired cardiac adaptive response to pressure overload in KO mice. In Nlrp3-deleted hearts, the catalytic activation of caspase-1 and the proteolysis of pro-IL-1β were suppressed compared with those in WT hearts. These results indicated that active IL-1β production via NLRP3 inflammasome activation is important for adaptive cardiac hypertrophy. It was reported that extracellular ATP activates the NLRP3 inflammasome via the P2X7 receptor. We found that pharmacological inhibition of P2X7 receptor or depletion of extracellular ATP in WT mice resulted in impaired adaptive cardiac hypertrophy after TAC (n=6). ATP is one of neurotransmitters released from the sympathetic nerve terminals. Sympathetic suppression with clonidine, an α2-adrenergic receptor agonist, impaired cardiac adaptive response after TAC in WT mice (n=6), suggesting that ATP from the sympathetic nerve terminals is important for NLRP3 inflammasome activation in the heart during pressure overload. We also found that ablation of afferent nerves from the heart by capsaicin treatment led to impaired active IL-1β production after TAC in WT mice.
Conclusions: Our results suggest that NLRP3 inflammasome activation through the heart-brain interaction contributes to adaptive cardiac hypertrophy in response to pressure overload. Our findings may provide the new perspectives on inflammation in cardiac hypertrophy.
- © 2013 by American Heart Association, Inc.