2. Academic Validation
  3. Glycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction

Glycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction

  • J Mol Cell Cardiol. 2020 Dec;149:82-94. doi: 10.1016/j.yjmcc.2020.09.009.
Shuhui Wang 1,  Xueling Su 1,  Lina Xu 1,  Cheng Chang 1,  Yu Yao 2,  Sumra Komal 1,  Xuexiang Cha 1,  Mingxi Zang 3,  Xinshou Ouyang 4,  Lirong Zhang 5,  Shengna Han 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 2 Undergraduate, Student of Class 2015, Department of Clinical Medicine, Zhengzhou University, Zhengzhou 450052, China.
  • 3 Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4 Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: [email protected].
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: [email protected].
PMID: 32991876 DOI: 10.1016/j.yjmcc.2020.09.009
Abstract

Inflammasome-promoted sterile inflammation following cardiac damage is critically implicated in heart dysfunction after myocardial infarction (MI). Glycogen synthase kinase-3 (GSK-3β) is a prominent mediator of the inflammatory response, and high GSK-3 activity is associated with various heart diseases. We investigated the regulatory mechanisms of GSK-3β in activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model with successful induction of MI on days 2-28. An in vitro investigation was performed using newborn rat/human cardiomyocytes and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. GSK-3β inhibition markedly improved myocardial dysfunction and prevented remodeling, with parallel reduction in the parameters of NLRP3 inflammasome activation after MI. GSK-3β inhibition reduced NLRP3 inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes. GSK-3β's interaction with activating signal cointegrator (ASC) as well as GSK-3β inhibition reduced ASC phosphorylation and oligomerization at the tissues and cellular levels. Taken together, these data show that GSK-3β directly mediates NLRP3 inflammasome activation, causing cardiac dysfunction in MI.

Keywords

ASC; Cardiac fibroblasts; Glycogen synthase kinase 3; Myocardial infarction; NLRP3 inflammasome.

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