Abstract
Myocardial infarction activates the NLRP3 inflammasome that triggers the inflammatory caspase‐1 activation and the IL‐1β maturation. We studied whether a specific inhibitor of the NLRP3 inflammasome, CP‐456,773, can attenuate cardiac sympathetic reinnervation and fatal arrhythmias in a rat model of myocardial infarction. Male Wistar rats were subjected to coronary ligation and then randomized to either saline or CP‐456,773 in in vivo and ex vivo studies. Postinfarction was associated with the activation of NLRP3 inflammasome components and increased the protein and expression of IL‐1β. Immunohistochemical staining of the border zone after infarction revealed macrophages positive for IL‐1β at 3 days post‐MI. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle‐treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with CP‐456,773 significantly attenuated myocardial levels of mature caspase‐1 and IL‐1β proteins although there were similar levels of NLRP3 and ASC proteins. CP‐456,773 did not affect NLRP3, ASC, caspase‐1 and IL‐1β expression at mRNA levels. Sympathetic hyperinnervation was blunted after administering CP‐456,773, as assessed by immunofluorescent analysis and western blotting and real‐time quantitative RT–PCR of nerve growth factor. Arrhythmic scores in the CP‐456,773‐treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed no additional effect of anti‐IL‐1β antibody on attenuated levels of NGF compared with CP‐456,773 alone. CP‐456,773 protects ventricular arrhythmias by attenuating sympathetic innervation via NLRP3 inflammasome/IL‐1β‐dependent pathways, which converge through the attenuated formation of nerve growth factor in infarcted rats.Support or Funding InformationnilThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
