Taurine alleviates sympathetic innervation by inhibiting NLRP3 inflammasome in post-infarcted rats

Taurine (2-aminoethanesulphonic acid) is the most abundant organic molecule in the human body.1 Although it can be synthesized endogenously, mammals cannot adequately synthesize taurine and depend on dietary sources to satisfy requirements. Taurine is found in very high concentration in the heart.2 Taurine has been shown to be involved in many diverse pathophysiological functions of the heart, including the balance of neurotransmitters and anti-inflammation3; however, the mechanisms of these actions are not yet understood. During myocardial infarction (MI), neutrophils secrete latent forms of proteolytic enzymes, and these enzymes are then activated by myeloperoxidase-produced hypochlorous acid.4 Taurine undergoes halogenation in phagocytes and is converted to taurine chloramines, a more stable and less toxic anti-inflammatory mediator.4 By contrast, in a rat model, Allo et al5 showed that taurine deficiency protected the heart against ischemia/reperfusion-induced injury. Therefore, further studies are warranted to investigate the potentially beneficial effects of taurine in ischemic heart injury. Cardiac sympathetic hyperinnervation post-MI has been correlated with an increased incidence of fatal arrhythmias. Fatal ventricular arrhythmias are a common complication after MI, accounting for almost 50% of cases of sudden cardiac death in survivors of MI, and increased sympathetic nerve density has been shown to be the main cause.6 Cardiac remodeling post-MI is an intricate inflammatory process that involves many signaling pathways. In addition, inflammation induced by MI has been shown to upregulate nerve growth factor (NGF), which plays an important role in sympathetic sprouting and sympathetic hyperinnervation.7 The proinflammatory IL-1β has been shown to regulate the synthesis of NGF in peripheral nerves8 and fibroblasts.9 Thus, the inflammatory response after MI may contribute to sympathetic nerve by a cytokine ⁄neurotrophin axis. Inflammation plays an important role in the wound healing process after injury. An exaggerated inflammatory response is believed to be responsible for the increased morbidity and mortality after MI. Inflammasomes are innate immune signaling pathways and cytosolic multiprotein complexes that are present mainly in macrophages. The structure of all inflammasomes is similar, typically containing nucleotide-binding oligomerization domain-like receptor sensor (NLRP3), effector (caspase-1), adapter (Apoptosis-Associated Speck-Like Protein Containing CARD [ASC]), and substrate (proinflammatory cytokines pro-IL-1β/18) components. Of these components, the sensors recognize danger signals released during tissue injury such as damage-associated molecular pattern molecules (DAMPs) and stress (such as urate crystal, extracellular Adenosine triphosphate, cell debris, and β-amyloid). DAMPs are associated with activation of NF-κB.10,11 The activation of NF-κB is extremely important for inflammatory signaling pathway after MI. The inhibition of NLRP3 by small interfering RNA has been shown to prevent the activation of inflammasomes and cardiac cell death, thereby ameliorating myocardial remodeling.12,13 Therefore, the pharmacological inhibition of NLRP3 may be a new strategy to attenuate ischemia/reperfusion injury post-MI. Recently, taurine has been shown to inhibit NLRP3 inflammasome in arsenic trioxide–induced liver diseases.14 Furthermore, taurine inhibited NF-κB nuclear translocation,15 an upstream regulator of the NLRP3 inflammasome. Thus, it is reasonable to speculate that besides formation of taurine haloamine, taurine may play an anti-inflammatory role by inhibition of NLRP3 inflammasome. MI was associated with decreased intracellular taurine content in the heart through attenuated expression of taurine transporters.16 Exogenous taurine supplement upregulated taurine transporter expression and increased the intracellular content of taurine. However, whether taurine administration efficiently regulates sympathetic nerve remodeling after MI remained unclear. Given the regulation of NGF secretion is in a cell-specific and tissue-specific manner,17 the effect of IL-1β on NGF secretion in myocardium should be clarified. Thus, we assessed (1) the effect of chronic administration of taurine on sympathetic reinnervation and ventricular arrhythmias, (2) the relative contribution of taurine haloamine and NLRP3 inflammasome inhibition in taurine-mediated anti-inflammation, and (3) the effect of IL-1β on myocardial NGF expression in a rat MI model.