Glycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction
Graphical abstract
Introduction
Myocardial infarction (MI) is the leading cause of death worldwide [1]. Although modern healthcare has reduced the rate of acute infarction-related mortality, the prevalence of heart failure continues to increase. Therefore, novel therapeutic strategies to repair infarcted hearts are urgently needed.
MI is closely related to sterile inflammation, which is a critical condition for tissue healing and may lead to excessive heart damage and maladaptive ventricular remodeling [2]. Growing evidence indicates that the inflammasome, a large multiprotein complex in the cytosol that may induce caspase-1 activation, plays a key role in sterile inflammation. We have an understanding of many inflammasome functions [3], of which the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has been extensively studied. It has also been shown that the NLRP3 inflammasome plays an indispensable role in the development and progression of aseptic inflammation [4].
When NLRP3 is activated, it binds to the activating signal cointegrator (ASC) adaptor molecule and aggregates with pro-caspase-1, which are components of the NLRP3 inflammasome [5]. The NLRP3 inflammasome converts pro-caspase-1 to caspase-1, which catalyzes the conversion of pro-IL-1β to its mature product IL-1β. IL-1β secretion from cells causes inflammation and tissue damage [6]. IL-1β plays an important role in the inflammatory response following MI by regulating immune cell recruitment, cytokine production, and extracellular matrix turnover [7]. Recent research has shown that early IL-1β elevation impairs cardiac function, reduces left ventricular ejection fraction (LVEF), and induces hypertrophy [[8], [9], [10]]. In preclinical and clinical studies, inhibition of IL-1 signaling after MI has been shown to improve left ventricular function and reduce the incidence of heart failure [[11], [12], [13]].
Glycogen synthase-3β (GSK-3β) is a multifunctional serine/threonine kinase that was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate various cell functions including cellular structure, growth, motility, metabolism, and survival [14]. Studies on various signal transduction pathways, including Wnt/wingless, nuclear factor-kappa B, insulin, and apoptotic signaling, have shown that cell survival is largely dependent on GSK-3β [15]. The role of GSK-3β in myocyte biology and disease has been studied [[16], [17], [18]]. GSK-3β also contributes to cardiac hypertrophy [19] and heart failure [20]. Furthermore, if GSK-3β activity is inhibited, myocardial ischemia-reperfusion and doxorubicin-induced heart damage are improved and restored to some extent [21].
Recent reports have shown that GSK-3β plays a key role in controlling the inflammatory immune response [22,23]. Moreover, GSK-3β inhibitors decrease IL-1β expression [22]. Although GSK-3β is involved in activation of the NLRP3 inflammasome in various diseases [[24], [25], [26]], it is unclear whether GSK-3β regulates activation of the NLRP3 inflammasome in MI.
Accordingly, we evaluated the mechanisms involved in GSK-3β-mediated activation of the NLRP3 inflammasome after MI. GSK-3β may be a novel therapeutic target for cardiovascular disease.
Section snippets
Animals
Male Sprague-Dawley rats (220–240 g; Experimental Animal Center of Zhengzhou University, Zhengzhou, Henan, China) were kept under standard conditions. Animal experiments were approved by the Animal Experiments Committee of Zhengzhou University and the Experimental Animal Center of Zhengzhou University (Permit No. SYXK [YU] 2011–0001) and conformed to the Guidelines for the Care and Use of Laboratory Animals (NIH Publication, 2011). All of the studies followed editorial guidelines for
SB216763 inhibits GSK-3β activation in ischemic hearts
Rats were treated with SB216763 at 1 h before MI surgery and once daily thereafter. To evaluate GSK-3β activation, we first observed the mRNA expression of GSK-3β in the LV at various time points. In the ischemic zone, MI induced an increase in GSK-3β mRNA expression on day 2 post-MI (Fig. 1A), with maximum expression observed on day 7 post-MI (Fig. 1B) and a slow decrease thereafter (day 28) (Fig. 1C). In the border zone, MI increased GSK-3β mRNA expression on day 7 post-MI; this increase was
Discussion
GSK-3β is an important therapeutic target in a variety of pathologies [37]. Several studies indicate that the inhibition of GSK-3β before ischemia or reperfusion has marked cardioprotective effects [38]. Our study found that the inhibition of GSK-3β conferred cardioprotection by attenuating activation of the NLRP3 inflammasome in MI-induced rats. Moreover, GSK-3β affects the activation of NLRP3 inflammasomes by affecting the phosphorylation of ASC, and GSK-3β inhibition reduced cytoplasmic
Conclusions
Our results identified a novel mechanism through which GSK-3β regulates myocardial fibrotic remodeling in the infarcted heart of rats. GSK-3β may exert these effects via the direct regulation of NLRP3 inflammasome activation. Clinically, pharmacological inhibitors targeting GSK-3β show potential for the treatment of MI.
The following is the supplementary data related to this article.
Disclosures
None.
Declaration of Competing Interest
None.
Acknowledgments
The National Natural Science Foundation of China (No. 81670311) supported this work.
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