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Signaling pathways of inflammation in myocardial ischemia/reperfusion injury

Hu, Shi-Yu1,2,3; Yang, Ji-E1,2,3; Zhang, Feng1,2,3,∗

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doi: 10.1097/CP9.0000000000000008
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Abstract

Introduction

Primary percutaneous coronary intervention (PCI) is the gold standard in the treatment of myocardial infarction (MI). Ample evidence showed that restoring blood flow through the occluded coronary artery with PCI could reduce mortality and morbidity in MI patients. A major problem with PCI is the secondary ischemia/reperfusion (I/R) injury, which contributes to about 50% of the overall functional loss of the heart[1].

Many factors contribute to the I/R injury, including inflammation, oxidative stress, and cell death[2]. Among these factors, inflammation plays an important role in initiating and aggravating the injury[3]. After reperfusion, myocardiocytes and recruited inflammatory cells can be “activated” by the binding of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to pattern recognition receptors (PRRs), with subsequent the activation of a variety of signaling pathways, and ultimately overexpression of many pro-inflammatory mediators[4]. This review summarized the recent advances in understanding the signaling pathways that underlie exaggerated inflammation during MI/RI and novel therapeutic targets in MI/RI treatment.

Signaling pathways leading to NF-κB

Nuclear factor kappa-B (NF-κB) is a family of transcriptional factors that consist of Rel (cRel), RelA (p65), RelB, NF-κB1 (p50), and NF-κB2 (p52)[5]. Activation of NF-κB is an early event during MI/RI[6], and upregulate the expression of a variety of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, chemokines (eg, MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and inducible enzymes that produce secondary inflammatory mediators such as COX-2 and induced NO synthase (iNOS)[7]. A study in rats showed arginase-2 could protect myocardium from MI/RI by inhibiting the NF-κB/TNF-α pathway[8]. Baicalein, a flavonoid found in Scutellariae radix and Scutellariae baicalensis, in combination with palmitoylethanolamide also produces anti-inflammatory effect by inhibiting NF-κB in a rat model of MI/RI[9]. Minocycline, a tetracycline antibiotic, could alleviate inflammation by inhibiting NF-κB and up-regulating the MCP-induced protein-1[10]. Polyphyllin I[11] and triptolide[12] can alleviate inflammation by inhibiting NF-κB and decreasing iNOS expression in a rat model of MI/RI. NF-κB also aggravates cell death by promoting the expression of pro-apoptosis factors, including Bax, cleaved caspase-9, and cleaved caspase-3[13]. Cyclosporin A produces anti-inflammatory and anti-apoptotic effects by inhibiting NF-κB in H2O2-induced cell injury[14]. In contrast, Rno-microRNA-30c-5p promotes MI/RI by activating the NF-κB pathway[15].

Upon binding with inhibitor of nuclear factor kappa-B (IκB), NF-κB dimers in the cytoplasm are inactivated. Several pathways promote the phosphorylation of IκB-α and the release of NF-κB by IκB kinase (IKK) (Figure 1)[16]. NF-κB is downregulated by inhibiting IKK or p-IκB-α expression. In a study in rat model of MI/RI, zinc finger protein A20, also known as TNF-α induced protein 3 (TNFAIP3), could inhibit IKK activity, and ginkgolide B could attenuate inflammation mediated by the A20/NF-κB pathway[17]. Extracts from silibinin[18] and shenlian[19] have been shown to inhibit the IKK-β activity, IκB-α phosphorylation and NF-κB p65 subunit translocation. Apigenin-7-O-b-D(600-p-coumaroyl)-glucopyranoside (APG), a flavonoid glycoside found in C. tangutica, could inhibit NF-κB translocation by decreasing the expression level of p-IκB-α in both MI/RI rat model and OGD/R-induced NRCM injury model[20].

F1
Figure 1:
Signaling pathways that activate NF-κB.Inactivated NF-κB dimer binds to IκB-α in the cytoplasm. Activated IKK phosphorylates IκB-α and releases NF-κB to promote the expression of a variety of proinflammatory cytokines in the nucleus. Upon activation by DAMPs, the intercellular domain of TLR, TIR, binds to Myd88 to activate TRAF6. Another domain of TLR, TRIF, activates TRAM, and facilitates the activation of TRAF3/6. TRAF3 promotes the combination of RIP1 and TAK1, and activates JNK. MAPKs (eg, JNK and p38-MAPK) activate NF-κB as well as c-Jun-AP-1. p38-MAPK is activated by LTB4-BLT1 binding, RhoA/ROCK pathway, and DAMPs/AGEs-RAGE binding.

Specific pathways that activating NF-κB are discussed below.

TLR4/Myd88/NF-κB signaling pathway

Toll-like receptors (TLRs), a type of PRRs, have been implicated in MI/IR[21–23]. TLR4 has an intracellular Toll-interleukin (IL)1 receptor (TIR) domain that interact with the universal adaptor protein myeloid differentiation factor 88 (MyD88) and a TIR domain containing adaptor inducing interferon (IFN)-β (TRIF). When TLR4 is activated, TLR4 and MyD88 are connected by the TIR domain-containing adaptor protein (TIRAP/Mal), and (TRIF) related adaptor molecule (TRAM) initiates the interaction between the TIR domain and TRIF to facilitate the recruitment of the downstream TNF receptor-associated factor (TRAF6). The MyD88/TRAF6 pathway activates IKK and the NF-κB pathway (Figure 1)[21,24]. A PLGA-NP nanoparticle that delivers TAK-242-NP, a chemical inhibitor of TLR4 intracellular domain to specifically target the cardiomyocyte produces anti-inflammatory effect in a mouse model of MI/RI[25]. Deleted in esophageal cancer 1 (DEC1) functions as a basic helix-loop-helix transcription factor, and downregulation of DEC1 by RNA interference could attenuate inflammation by inhibiting the TLR4/NF-κB signaling pathway[26]. Inhibiting of the TLR4/NF-κB signaling pathway has been implicated in the cardioprotective effect of remote ischemic preconditioning (RIPC)[27]. A number of molecules, including HSP90[28], salidroside[29], resveratrol,[30] and tilianin-loaded micelles[31] have been found to inhibit inflammation in MI/RI by targeting TLR4/NF-κB pathway. Inhibition of the TLR4/NF-κB signaling pathway has also been implicated in several Chinese traditional medicines, including Guizhi Gancao Decoction (GGD)[32], Shuxuening injection[33], and Safflower yellow injection[34].

Radioprotective protein 105(RP105) is another member of the TLR family that lacks a TIR domain. RP105 acts as an inhibitor of TLR4 in macrophages and dendritic cells[35–37]. Downregulation of miR-327 could up-regulate RP105 to alleviate inflammation in MI/RI[38], whereas myeloid differentiation protein 1 (MD1) could bind to RP105 to inhibit inflammation[39,40].

TLRs must be activated by PAMPs or DAMPs. Upon MI/RI, cardiomyocytes release a variety of PAMPs and DAMPs, including HMGB1, ROS, and HSP. Upon MI, non-acetylated fr-HMGB1 is secreted by activated immune cells or released from necrotic cells. ROS generated by reperfusion oxidizes fr-HMGB1 to ds-HMGB1, which in turn binds to RAGE, TLR2 and TLR4 to activate the NF-κB pathway[41,42]; such action could be blocked by an anti-HMGB1 neutralizing antibody[43]. HMGB1 inhibition has also been implicated in the anti-inflammatory effects of quercetin[44], lncRNA TUG1[45], picroside II[46], ghrelin[47], dexmedetomidine,[48–50] and tanshinone IIA sodium sulfonate (TSS)[51] in MI/RI.

MAPKs/NF-κB signaling pathway

The mitogen-activated protein kinases (MAPKs) family, including p38-MAPK, c-Jun N-terminal protein kinase (JNK)1/2 and ERK1/2, have also been implicated in inflammation upon MI/RI (Figure 1).

JNK and p38-MAPK aggravate the inflammation in MI/RI. AMP-activated protein kinase (AMPK) is an energy sensor that regulates the intracellular ATP to AMP ratio; it is stimulated by mitochondrial dysfunction and energy deficiency in MI/RI. AMPK modulates the inflammatory response through JNK/NF-κB signaling[52,53]. C1q/tumor necrosis factor-related protein9 (CTRP9) could activate AMPK to attenuate inflammation[54]. Diosgenin, a precursor of steroid hormones, could attenuate inflammation by inhibiting JNK/NF-κB signaling[55]. HSP90 inhibits the JNK/NF-κB pathway, and by doing so, plays a vital role in the cardioprotective effect of ischemic postconditioning (IPC)[56]. MiR155 binding to receptor BAG5 could aggravate inflammation by activating JNK/NF-κB pathway[57]. Allicin[58] and β-cryptoxanthin[59] inhibit p38-MAPK/NF-κB pathway whereas phospholipase C-1[60] promotes p38-MAPK/NF-κB. Flavonoids extracted from Rosa rugosa could alleviate inflammation by inhibiting the p38-MAPK/NF-κB and JNK/NF-κB pathway[61]. NOD2, a member of the NLR family, has also been shown to aggravate inflammation through the MAPK/NF-κB pathway, such effect could be attenuated by the TNF-α-inducible protein 8-like 2 (TIPE2)[62].

In contrast to the MAPK/NF-κB pathway, ERK mainly exerts a protective effect during MI/RI by enhancing the expression of Bcl-2 and attenuating the expression of Bax[63]. This is, however, outside the topic of this review.

TLR4 activation promotes the interaction between the TIR domain and TRIF to facilitate the recruitment of the TRAF3 as well as TRAF6. TRAFs promote the recruitment and ubiquitylation of receptor interacting protein 1 (RIP1) that in turn bind to transforming growth factor-β-activated kinase 1 (TAK1) and MAPKs (Figure 1). Inhibiting TRAF3 expression could attenuate inflammation by restraining JNK in MI/RI[64].

Rho-associated protein kinase (ROCK) is a serine/threonine protein kinase of the Rho family.

Rho A is a small GTP-binding protein that acts as the upstream protein of ROCK. Y-27632, a Rho-kinase inhibitor, has been shown to inhibit the MAPK/NF-κB pathway through inhibiting the RhoA/ROCK pathway[65], suggesting that RhoA/ROCK pathway may regulate MAPK/NF-κB activation (Figure 1). Vitamin D attenuates inflammation in MI/RI by inhibiting RhoA/ROCK/NF-κB pathway, but independent of the MAPKs[66].

RAGE is a transmembrane receptor for advanced glycation end products (AGEs), and its activation can aggravate inflammation in MI/RI, especially in under hyperglycemic conditions (Figure 1)[67]. Mangiferin has been shown to alleviate inflammation caused by MI/RI by modulating the AGE-RAGE/MAPK/NF-κB pathway[68]. Binding of HMGB1 (especially ds-HMGB1) to RAGE activates MAPK and promotes the inflammatory effect of the NF-κB pathway[42].

The transcription of c-Jun-AP-1 complex is promoted by p38-MAPK through activation of CREB binding protein (CBP) and subsequent AP-1 upregulation, as well as activation of Jun by JNK (Figure 1). MicroRNA-22 has been shown to attenuate inflammation in MI/RI via suppressing the p38-MAPK/CBP/c-Jun-AP-1 signaling pathway[69]. In contrast, TRAF3IP2 aggravates inflammation by activating the JNK/Jun/c-Jun-AP-1 signaling pathway[70].

Other possible signaling pathways leading to NF-κB activation

The Wnt pathway is involved in inflammation mediated by the NF-kB pathway and is inhibited by NF-κB via negative feedback. MiR-1275 mimics have been shown to protect cardiomyocytes from inflammation via inhibiting the Wnt/NF-κB pathway[71]. Wnt has also been implicated in the cardioprotective effects of frizzled-related protein 5[72].

During MI/RI, inflammatory cells (eg, neutrophils) are recruited and activated, and arachidonic acids are metabolized by 5-lipoxygenase 5 (5-LOX) and 5-lipoxygenase activating protein (FLAP) to eicosanoids such as leukotriene B4 (LTB4)[73]. LTB4 binds to receptor BLT1 and promotes the phosphorylation of IKK and IκB-α which in turn activate NF-κB[74]. LTB4-BLT1 could also activate MAPKs/NF-κB (Figure 1)[74]. 11-Keto-β-boswellic acid, a selective 5-LOX inhibitor has been shown to protect the heart from MI/RI via inhibiting the 5-LOX/LTB4-BLT1/NF-κB pathway[75]. Such protective effects could be blocked by the BLT1 antagonist LSN2792613[76].

CaMKII is a serine/threonine protein kinase, whereas ASK1 belongs to the MAPK family. MicroRNA-145 has been shown to attenuate the inflammation in MI/RI via inhibiting the CaMKII/ASK1/NF-κB pathway[77].

CD40 is a member of the tumor necrosis factor receptor (TNFR) family with a cytoplasmic domain that interact with TRAFs[78]. Many inflammatory factors, including TNF-α, IL-1, IFN-γ, and CD40 ligand (CD40L), regulate the expression of CD40, and ultimately activate NF-κB and MAPKs via TRAFs[79]. Ginkgolide C has been shown to alleviate MI/RI inflammation via inhibiting the CD40/NF-κB pathway[80].

Signaling pathways that suppress NF-κB

Phosphoinositide-3 kinase (PI3K) is a key regulator of serine/threonine kinase (Akt)[81], which in turn downregulate the expression of IκB (Figure 2)[82]. A variety of molecules, including TRIM59[83], flavonoids[84], SH2B1[85], progranulin[86], epigallocatechin[87], gypenoside[88], and berberine[89], have been shown to attenuate inflammation in MI/RI via activating the PI3K/Akt signaling pathway. Studies have implicated the PI3K/Akt signaling pathway in the anti-inflammatory effects of baicalin[90] and 6-gingerol[91] in MI/RI. It must be emphasized that the PI3K/Akt signaling pathway also possess anti-apoptotic and anti-oxidative effects in MI/RI although this review does not address these issues.

F2
Figure 2:
Signaling pathways with cardioprotective effect.PI3K/AKT pathway inhibits NF-κB and activates the Nrf2/HO-1 pathway. JAK2/STAT3 pathway activates GSK-3, inhibits mPTP and activates PI3K/AKT pathway. ERK, a member of MAPKs family, has anti-apoptotic effect. Upon binding with Keap-1, Nrf2 exits as its inactive form in the cytoplasm. When activated, Nrf2 dissociates from Keap-1 and translocates to the nucleus where it binds to ARE and promotes the expression of HO-1, and ultimately anti-inflammatory effect. PPARγ bind to RXR, activates PPREs, and promotes the expression of PI3L/AKT pathway, JAK2/STAT3 pathway, and ERK. PPREs could also inhibit NF-κB. PPARγ in the cytoplasm activates PGC-1α to facilitate the release of Nrf2 from Keap-1.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor, and has been implicated in MR/RI in at least two ways. First, PPARγ binds to the receptor of 9-cis-retinoic acid (RXR), and this complex interacts with peroxisome proliferator response elements (PPREs), which is present in the promoter areas of target genes. The trans-activation way produces cardioprotective effect by activating the protective pathways, including the PI3K/Akt pathway and ERK1/2 pathway, as well as the JAK2/STAT3 pathway as describe below. Second, PPARγ could suppress NF-κB activation (Figure 2)[92]. The underlying mechanisms of these actions are unknown, but may involve direct suppression of NF-κB or MAPKs by PPARγ[93]. Rosmarinic acid[94] and irebesartan[95] have been shown to alleviate inflammation by activating PPARγ and inhibiting NF-κB.

Sphingosine 1-phosphate (S1P) has been shown to elevate intracellular cAMP levels and inhibit NF-κB, and C1q/TNF-related protein-1 has been shown to alleviate inflammation during MI/RI by activating the S1P/cAMP pathway[96].

Silent information regulator 1 (SIRT1) could inhibit NF-κB by interacting with transcription factors[97]. SIRT1 activation has been implicated in the anti-inflammatory effect of berberine in MI/RI[98].

NLRP3 inflammasome

NLRP3 inflammasome is a member of the nod-like receptor (NLR) family that consists of a nucleoside binding oligomeric domain-like receptor (NLRP3), a caspase recruitment domain (ASC), and pro-caspase-1. NLRP3 induces translocation and activation of caspase-1, which in turn cleaves the precursors of IL-1β and IL-18 to form active IL-1β and IL-18[99]. The pro-inflammatory effects of NLRP3 inflammasome in MI/RI could be attenuated by the NLRP3 inhibitor OLT1177[100].

Caspase-1 can also cleave the GSDMD, a member of the gasdermin family, to release its functional pore-forming N-terminal to facilitate the release of IL-1β and IL-18 and induce pyroptosis. Mir-495[101] and lncRNA HULC[102] have been shown to inhibit inflammation and pyroptosis via suppressing NLRP3 inflammasome. β-Asarone[103], a major active component of traditional Chinese medicine – Acorus tatarinowii Rhizoma, and gastrodian[104] have been shown to alleviate inflammation and pyroptosis via the NLRP3 inflammasome.

NLRP3 inflammasome activation requires two steps: priming and activating/triggering[105]. Upon MI, many DAMPs are released from necrotic tissues and bind to TLR4 to activate NF-κB through the TLR4/Myd88/NF-κB pathway. Pro-IL-1α released from necrotic tissues bind to IL-R1 to produce conformational change of IL-R1 and IL-R3. The intracellular domain of these receptors contains the TLR domain (known as Toll-IL-1-receptor) that could bind to Myd88 to activate NF-κB. Activated NF-κB promotes the transcription and translation of the precursors of IL-1β, IL-18, and the components of NLRP3 inflammasome. This priming step does not activate the NLRP3 inflammasome itself. In the second activating step, purinoreceptor 2X7 (P2X7R) is activated by increased extracellular ATP upon MI/RI and causes K+ efflux. The K+ efflux and intracellular ROS activate the NLRP3 inflammasome and subsequent cascade of events (Figure 3)[105]. Lipopolysaccharide (LPS) has been shown to aggravate MI/RI via activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis[106]. Biochanin A has been found to inhibit the TLR4/NF-κB pathway via inhibition of NLRP3 inflammasome[107]. Cathelicidin has been shown to aggravate inflammation in MI/RI via the P2X7R/NLRP3 inflammasome pathway[108].

F3
Figure 3:
The NLRP3 inflammasome.NLRP3 inflammasome activation involves two steps. In the first step of priming, DAMPs are released from necrotic tissues uponMI/RI and bind to the TLR4 to activate NF-κB through the TLR4/Myd88/NF-κB pathway. The binding of pro-IL-1α and IL-R can also activate NF-κB. Activated NF-κB promotes the transcription and translation of the precursors of IL-1β, IL-18, and the components of NLRP3 inflammasome. In the second step of activating, purinoreceptor 2X7 (P2X7R) are activated by increased extracellular ATP and causes K+ efflux. The K+ efflux and intracellular ROS activate NLRP3 inflammasome and cleave pro-caspases-1 to caspase-1. Caspase-1 cleave pro-IL-1β, pro-IL-18, and GSDMD to their functional type IL- 1β, IL-18, and N-terminal of GSDMD, which in turn forms a GSDMD pore on the cell surface to facilitate the release of IL-1β and IL-18 and to induces pyroptosis.

JAK2/STAT3 signaling pathway

The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) play critical roles in inflammation[109], apoptosis[110], and oxidative stress[111]. Among the four types of JAKs and seven types of STATs[112], the JAK2/STAT3 signaling is the most studied in the context of MI/RI, but its functional role still remains controversial.

One hypothesis proposes that the JAK2/STAT3 pathway induces phosphorylation and inactivation of glycogen synthase kinase-3 (GSK-3) to inhibit mitochondrial permeability transition pore (mPTP), as well as facilitates the PI3K/Akt pathway to produce cardioprotective effect[113]. PPARγ is an upstream receptor of the JAK2/STAT3 pathway and cilostazol has been shown to possess protective effect via this mechanism (Figure 2)[114]. The JAK2/STAT3 pathway has been implicated in a variety of molecules, including egr-1[115], eriodictyol[116], JLX001[117], N(2)-L-alanyl-L-glutamine[118], and ANXA1[119]. YB1 has been shown to produce cardioprotective effect by interacting with protein inhibitor of activated STAT3 (PIAS3) mRNA and phosphorylation of STAT3[120].

On the other hand, IL-23[121] has been shown to activate the JAK2/STAT3 pathway and promote the differentiation of memory CD4+ T cells to Th17 cells[122]. IL-17A is an important proinflammatory factor that stimulate the synthesis and release of IL-1, TNF-α, IL-6, and C-reactive protein[123]. As described earlier, TLR4/TRIF activates the transcriptional activity of interferon regulating factor 3 (IRF3) and the TLR4/TRIF/IRF3 signaling pathway to upregulate IFN-β, which in turn is recognized by its surface receptor to trigger the activation and transduction of JAK/STAT1 signaling. MicroRNA-421 has been shown to attenuate inflammation by inhibiting the TLR4/JAK2/STAT3 pathway[124]. Baicalin has been shown to alleviate inflammation in MI/RI via inhibiting the JAK2/STAT3 pathway[125] and PAFR-deficiency suppresses the JAK1/STAT1 pathway to attenuate inflammation[126].

The effects of HSP70 on STAT3 expression is controversial and inconsistent in cell and animal experiments[127], and more studies are needed.

Nrf2/HO-1 signaling pathway

Heme oxygenase (HO-1) protects cardiomyocytes via its anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-arrhythmic actions[128,129]. HO-1 gene therapy in a porcine model confirmed the anti-inflammatory effects of HO-1[130]. HO-1 is primarily regulated at the transcriptional level by the nuclear factor E2-related factor 2 (Nrf2)[131]. Under physiology conditions, Nrf2 is bound to its negative regulator, Kelch-like ECH associating protein 1 (Keap1), and localizes in the cytoplasm[132]. Upon oxidative stress, Nrf2 translocates to the nucleus and binds to the anti-oxidative stress response element (ARE) to promote the expression of HO-1 (Figure 2)[133]. IPC exerts its cardioprotective effect partially by the Nrf2/HO-1 signaling pathway[134]. Activation of the Nrf2/HO-1 pathway has also been implicated in the protective effects of the selective 5-LOX inhibitor 11-keto-β-boswellic acid[75], crocetin[135], and resveratrol[132], triptolide[136], as well as inhibition of ceramide de novo synthesis[137].

PI3K/Akt upregulates the Nrf2–ARE pathway and mediates HO-1 expression. Astragaloside IV[138] and Ginkgo biloba extract-761[139] have been shown to protect against MI/RI by upregulating the PI3K/Akt/Nrf2/HO-1 pathway.

Inhibition of MAPKs could activate Nrf-2 and ultimately inhibit NF-κB[140]. Mangiferin has been shown to produce anti-inflammatory effect by inhibit MAPKs and activating the Nrf-2/HO-1 pathway[141].

PPARγ coactivator-1α (PGC-1α) is an upstream molecule of Nrf2, and the PGC-1α/Nrf2 signaling is a potential target for cardioprotection in myocardial I/R injury (Figure 2)[142]. The cardioprotective effects of melatonin has been attributed to the PPARγ/PGC-1α/TNF-α pathway[143].

Conclusion

Inflammatory response to MI/RI involves a variety of signaling pathways, including the TLR4/Myd88/NF-κB, MAPK/NF-κB, PI3K/AKT/NF-κB, JAK2/STAT3, and Nrf-2/HO-1. The TLR4/Myd88/NF-κB, MAPK/NF-κB, and PI3K/AKT/NF-κB pathways are primarily pro-inflammatory, whereas JAK2/STAT3 pathway may produce both pro- and anti-inflammatory effects depending on the specific context. The Nrf-2/HO-1 pathway is clearly involved, but requires more investigation. Advances in these areas have provided novel targets for drug development, but have not yet produced solid treatments. Traditional Chinese medicines may provide valuable sources of lead compounds for R&D efforts.

Funding

This work was supported by the National Natural Science Foundation [grant numbers 81870268, 82000333] and Shanghai Clinical Research Center for Interventional Medicine [19MC1910300].

Author contributions

SYH and JEY conceived the study. SYH drafted the original manuscript and created the figures. All authors participated in revision of the first draft and collectively approved the final version of this manuscript. JEY and FZ provided financial support.

Conflict of interest statement

The authors declare that they have no financial conflict of interest with regard to the content of this manuscript.

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Keywords:

Inflammation; Ischemia/reperfusion injury; Myocardial infarction; NF-κB; NLRP3 inflammasome

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