Premium
Activation of autophagy protects against myocardial ischemic reperfusion injury by inhibition of NLRP3 inflammasome‐mediated pyroptosis and inflammatory responses in diabetic rats
Author(s) -
Wang Sheng,
Zhang Dengwen,
Ye Xiaodong,
He Yi,
Cai Yin,
Xia Zhengyuan
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb398
Subject(s) - pyroptosis , inflammasome , autophagy , medicine , myocardial infarction , streptozotocin , reperfusion injury , caspase 1 , inflammation , ischemia , proinflammatory cytokine , diabetes mellitus , pharmacology , cardiology , chemistry , endocrinology , apoptosis , biochemistry
Background Diabetic hearts are more vulnerable to ischemia/reperfusion injury (I/RI). The activation of NLRP3 inflammasome can mediate pyroptosis and inflammatory responses, which in turn exacerbate myocardial I/RI. Studies have demonstrated that activation of autophagy can eliminate excess reactive oxygen species (ROS) generation and alleviate myocardial I/RI in diabetes. However, the possible regulatory relationship between autophagy and NLRP3 inflammasome during diabetic myocardial I/RI is still unknown. Thus, the present study aimed to investigate whether the activation of autophagy can alleviate diabetic myocardial I/RI via inhibition of NLRP3 inflammasome‐mediated pyroptosis and inflammatory responses. Methods A dose of 60 mg/kg streptozotocin was given via tail vein injection to establish type 1 diabetes model in rats. The left anterior descending branch of the coronary artery was ligated for 30 minutes and then allowed for reperfusion for 2 hours to establish rat myocardial I/RI model. RapaLink‐1(1mg/kg, i.p.), the third‐generation mTOR inhibitor, was given 72 hours before inducing myocardial I/RI. The degree of I/RI was assessed by the measurement of plasma CK‐MB, cTnT, LDH, and myocardial infarction size. The expression of NLRP3, ACS, cleaved Caspase‐1, interleulin (IL)‐18, and IL‐1β in the myocardium, and the levels of IL‐18 and IL‐1β in the plasma were tested to assess the activation of inflammasome and inflammatory responses. In addition, LC3 □/□ and p62 were measured to evaluate the level of autophagy. Results Compared to non‐diabetic group, levels of cardiac autophagy were inhibited (decreased LC3 □/□ and increased p62) concomitant with activation of NLRP3 inflammasome (increased NLRP3, ASC, cleaved caspase‐1, IL‐18, IL‐1β) in diabetes. Also, more severe myocardial I/RI (elevated CK‐MB, cTnT, LDH, and larger infarction size) was seen in diabetic rats. Administration of RapaLink‐1 activated autophagy, inhibited NLRP3 inflammasome, and alleviated myocardial I/RI in diabetic rats. Conclusion The activation of NLRP3 inflammasome in the diabetic myocardium may be attributable to the inhibition of autophagy. The activation of autophagy may inhibit NLRP3 inflammasome activation and consequently alleviate myocardial I/RI in diabetes. Support or Funding Information The study was supported by Guangdong Natural Science Foundation (2018A030313535, Guangdong, China) and HMRF (05161826) of Hong Kong. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .