Secondary Logo

Journal Logo


Signaling pathways of inflammation in myocardial ischemia/reperfusion injury

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

Author Information
doi: 10.1097/CP9.0000000000000008
  • Open



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].

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.

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].

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].


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.


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.


[1]. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121–1135. doi: 10.1056/NEJMra071667.
[2]. Fröhlich GM, Meier P, White SK, et al. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013;34:1714–1722. doi:10.1093/eurheartj/eht090.
[3]. Saxena A, Russo I, Frangogiannis NG. Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res 2016;167:152–166. doi:10.1016/j.trsl.2015.07.002.
[4]. Timmers L, Pasterkamp G, de Hoog VC, et al. The innate immune response in reperfused myocardium. Cardiovasc Res 2012;94:276–283. doi:10.1093/cvr/cvs018.
[5]. Wan F, Lenardo MJ. The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives. Cell Res 2010;20:24–33. doi:10.1038/cr.2009.137.
[6]. Moss NC, Stansfield WE, Willis MS, et al. IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2007;293:H2248–2253. doi:10.1152/ajpheart.00776.2007.
[7]. Brigelius-Flohé R, Flohé L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid Redox Signal 2011;15:2335–2381. doi:10.1089/ars.2010.3534.
[8]. Huang XW, Pan MD, Du PH, et al. Arginase-2 protects myocardial ischemia-reperfusion injury via NF-κB/TNF-α pathway. Eur Rev Med Pharmacol Sci 2018;22:6529–6537. doi:10.26355/eurrev_201810_16067.
[9]. D’Amico R, Fusco R, Gugliandolo E, et al. Effects of a new compound containing Palmitoylethanolamide and Baicalein in myocardial ischaemia/reperfusion injury in vivo. Phytomedicine 2019;54:27–42. doi:10.1016/j.phymed.2018.09.191.
[10]. Yi Q, Tan FH, Tan JA, et al. Minocycline protects against myocardial ischemia/reperfusion injury in rats by upregulating MCPIP1 to inhibit NF-κB activation. Acta Pharmacol Sin 2019;40:1019–1028. doi:10.1038/s41401-019-0214-z.
[11]. Huang R, Shu J, Dai X, et al. The protective effect of polyphyllin I on myocardial ischemia/reperfusion injury in rats. Ann Transl Med 2020;8:644. doi:10.21037/atm-20-3371.
[12]. Yang B, Yan P, Yang GZ, et al. Triptolide reduces ischemia/reperfusion injury in rats and H9C2 cells via inhibition of NF-κB, ROS and the ERK1/2 pathway. Int J Mol Med 2018;41:3127–3136. doi:10.3892/ijmm.2018.3537.
[13]. Xu L, Zheng X, Wang Y, et al. Berberine protects acute liver failure in mice through inhibiting inflammation and mitochondria-dependent apoptosis. Eur J Pharmacol 2018;819:161–168. doi:10.1016/j.ejphar.2017.11.013.
[14]. Ma M, Ma X, Cui J, et al. Cyclosporin A protected cardiomyocytes against oxidative stress injury by inhibition of NF-κB signaling pathway. Cardiovasc Eng Technol 2019;10:329–343. doi:10.1007/s13239-019-00404-7.
[15]. Chen J, Zhang M, Zhang S, et al. Rno-microRNA-30c-5p promotes myocardial ischemia reperfusion injury in rats through activating NF-κB pathway and targeting SIRT1. BMC Cardiovasc Disord 2020;20:240. doi:10.1186/s12872-020-01520-2.
[16]. Han M, Chen XC, Sun MH, et al. Overexpression of IκBα in cardiomyocytes alleviates hydrogen peroxide-induced apoptosis and autophagy by inhibiting NF-κB activation. Lipids Health Dis 2020;19:150. doi:10.1186/s12944-020-01327-2.
[17]. Zhang R, Xu L, Zhang D, et al. Cardioprotection of Ginkgolide B on myocardial ischemia/reperfusion-induced inflammatory injury via regulation of A20-NF-κB pathway. Front Immunol 2018;9:2844. doi:10.3389/fimmu.2018.02844.
[18]. Chen YH, Lin H, Wang Q, et al. Protective role of silibinin against myocardial ischemia/reperfusion injury-induced cardiac dysfunction. Int J Biol Sci 2020;16:1972–1988. doi:10.7150/ijbs.39259.
[19]. Guo Y, Yang Q, Weng XG, et al. Shenlian extract against myocardial injury induced by ischemia through the regulation of NF-κB/IκB signaling axis. Front Pharmacol 2020;11:134. doi:10.3389/fphar.2020.00134.
[20]. Quan W, Ma S, Zhu Y, et al. Apigenin-7-O-β-d-(6″-p-coumaroyl)-glucopyranoside reduces myocardial ischaemia/reperfusion injury in an experimental model via regulating the inflammation response. Pharm Biol 2020;58:80–88. doi:10.1080/13880209.2019.1701043.
[21]. Vilahur G, Badimon L. Ischemia/reperfusion activates myocardial innate immune response: the key role of the toll-like receptor. Front Physiol 2014;5:496. doi:10.3389/fphys.2014.00496.
[22]. Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res 2011;108:1133–1145. doi:10.1161/CIRCRESAHA.110.226936.
[23]. Zhai Y, Ao L, Cleveland JC, et al. Toll-like receptor 4 mediates the inflammatory responses and matrix protein remodeling in remote non-ischemic myocardium in a mouse model of myocardial ischemia and reperfusion. PLoS One 2015;10:e0121853. doi:10.1371/journal.pone.0121853.
[24]. Vilahur G, Juan-Babot O, Peña E, et al. Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. J Mol Cell Cardiol 2011;50:522–533. doi:10.1016/j.yjmcc.2010.12.021.
[25]. Fujiwara M, Matoba T, Koga JI, et al. Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia-reperfusion injury by inhibiting monocyte-mediated inflammation in mice. Cardiovasc Res 2019;115:1244–1255. doi:10.1093/cvr/cvz066.
[26]. Xu W, Zhang K, Zhang Y, et al. Downregulation of DEC1 by RNA interference attenuates ischemia/reperfusion-induced myocardial inflammation by inhibiting the TLR4/NF-κB signaling pathway. Exp Ther Med 2020;20:343–350. doi:10.3892/etm.2020.8706.
[27]. Zhang J, Zhang J, Yu P, et al. Remote ischaemic preconditioning and Sevoflurane postconditioning synergistically protect rats from myocardial injury induced by ischemia and reperfusion partly via inhibition TLR4/MyD88/NF-κB signaling pathway. Cell Physiol Biochem 2017;41:22–32. doi:10.1159/000455815.
[28]. Zhang XY, Huang Z, Li QJ, et al. Role of HSP90 in suppressing TLR4-mediated inflammation in ischemic postconditioning. Clin Hemorheol Microcirc 2020;76:51–62. doi:10.3233/CH-200840.
[29]. Zhu L, Wei T, Gao J, et al. The cardioprotective effect of salidroside against myocardial ischemia reperfusion injury in rats by inhibiting apoptosis and inflammation. Apoptosis 2015;20:1433–1443. doi:10.1007/s10495-015-1174-5.
[30]. Li J, Xie C, Zhuang J, et al. Resveratrol attenuates inflammation in the rat heart subjected to ischemia-reperfusion: Role of the TLR4/NF-κB signaling pathway. Mol Med Rep 2015;11:1120–1126. doi:10.3892/mmr.2014.2955.
[31]. Wang Y, Wang Y, Wang X, et al. Tilianin-loaded reactive oxygen species-scavenging nano-micelles protect H9c2 cardiomyocyte against hypoxia/reoxygenation-induced injury. J Cardiovasc Pharmacol 2018;72:32–39. doi:10.1097/FJC.0000000000000587.
[32]. Gao Y, Song G, Cao YJ, et al. The Guizhi Gancao Decoction attenuates myocardial ischemia-reperfusion injury by suppressing inflammation and cardiomyocyte apoptosis. Evid Based Complement Alternat Med 2019;2019:1947465. doi:10.1155/2019/1947465.
[33]. Wang R, Wang M, Zhou J, et al. Shuxuening injection protects against myocardial ischemia-reperfusion injury through reducing oxidative stress, inflammation and thrombosis. Ann Transl Med 2019;7:562. doi:10.21037/atm.2019.09.40.
[34]. Li LM, Fu JH, Guo H, et al. Protective effect of safflower yellow injection against rat MIRI by TLR-NF-κB inflammatory pathway. Zhongguo Zhong Yao Za Zhi 2019;44:2566–2571. doi:10.19540/j.cnki.cjcmm.20190201.001.
[35]. Schultz TE, Blumenthal A. The RP105/MD-1 complex: molecular signaling mechanisms and pathophysiological implications. J Leukoc Biol 2017;101:183–192. doi:10.1189/jlb.2VMR1215-582R.
[36]. Liu B, Zhang N, Liu Z, et al. RP105 involved in activation of mouse macrophages via TLR2 and TLR4 signaling. Mol Cell Biochem 2013;378:183–193. doi:10.1007/s11010-013-1609-7.
[37]. Yang J, Yang C, Yang J, et al. RP105 alleviates myocardial ischemia reperfusion injury via inhibiting TLR4/TRIF signaling pathways. Int J Mol Med 2018;41:3287–3295. doi:10.3892/ijmm.2018.3538.
[38]. Yang Y, Yang J, Liu XW, et al. Down-regulation of miR-327 alleviates ischemia/reperfusion-induced myocardial damage by targeting RP105. Cell Physiol Biochem 2018;49:1049–1063. doi:10.1159/000493288.
[39]. Zhang YJ, Huang H, Liu Y, et al. MD-1 deficiency accelerates myocardial inflammation and apoptosis in doxorubicin-induced cardiotoxicity by activating the TLR4/MAPKs/nuclear factor kappa B (NF-κB) signaling pathway. Med Sci Monit 2019;25:7898–7907. doi:10.12659/MSM.919861.
[40]. Jiang X, Kong B, Shuai W, et al. Loss of MD1 exacerbates myocardial ischemia/reperfusion injury and susceptibility to ventricular arrhythmia. Eur J Pharmacol 2019;844:79–86. doi:10.1016/j.ejphar.2018.11.025.
[41]. Xia J, Xue JY, Chen K, et al. The role of high-mobility group box protein 1 in the signaling pathways of myocardial ischemia-reperfusion injury in rats. Zhonghua Yi Xue Za Zhi 2018;98:3268–3273. doi:10.3760/cma.j.issn.0376-2491.2018.40.011.
[42]. Raucci A, Di Maggio S, Scavello F, et al. The Janus face of HMGB1 in heart disease: a necessary update. Cell Mol Life Sci 2019;76:211–229. doi:10.1007/s00018-018-2930-9.
[43]. Zhou Y, Li Y, Mu T. HMGB1 neutralizing antibody attenuates cardiac injury and apoptosis induced by hemorrhagic shock/resuscitation in rats. Biol Pharm Bull 2015;38:1150–1160. doi:10.1248/bpb.b15-00026.
[44]. Dong LY, Chen F, Xu M, et al. Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-κB signaling pathway. Am J Transl Res 2018;10:1273–1283.
[45]. Shi H, Dong Z, Gao H. LncRNA TUG1 protects against cardiomyocyte ischaemia reperfusion injury by inhibiting HMGB1. Artif Cells Nanomed Biotechnol 2019;47:3511–3516. doi:10.1080/21691401.2018.1556214.
[46]. Li JZ, Xie MQ, Mo D, et al. Picroside II protects myocardium from ischemia/reperfusion-induced injury through inhibition of the inflammatory response. Exp Ther Med 2016;12:3507–3514. doi:10.3892/etm.2016.3841.
[47]. Sun N, Wang H, Wang L. Protective effects of ghrelin against oxidative stress, inducible nitric oxide synthase and inflammation in a mouse model of myocardial ischemia/reperfusion injury via the HMGB1 and TLR4/NF-κB pathway. Mol Med Rep 2016;14:2764–2770. doi:10.3892/mmr.2016.5535.
[48]. Chen J, Jiang Z, Zhou X, et al. Dexmedetomidine preconditioning protects cardiomyocytes against hypoxia/reoxygenation-induced necroptosis by inhibiting HMGB1-mediated inflammation. Cardiovasc Drugs Ther 2019;33:45–54. doi:10.1007/s10557-019-06857-1.
[49]. Zhang JJ, Peng K, Zhang J, et al. Dexmedetomidine preconditioning may attenuate myocardial ischemia/reperfusion injury by down-regulating the HMGB1-TLR4-MyD88-NF-кB signaling pathway. PLoS One 2017;12:e0172006. doi:10.1371/journal.pone.0172006.
[50]. Gao JM, Meng XW, Zhang J, et al. Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury by suppressing TLR4-MyD88-NF-κB signaling. Biomed Res Int 2017;2017:1674613. doi:10.1155/2017/1674613.
[51]. Pan Y, Qian JX, Lu SQ, et al. Protective effects of tanshinone IIA sodium sulfonate on ischemia-reperfusion-induced myocardial injury in rats. Iran J Basic Med Sci 2017;20:308–315. doi:10.22038/ijbms.2017.8361.
[52]. Chen X, Li X, Zhang W, et al. Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway. Metabolism 2018;83:256–270. doi:10.1016/j.metabol.2018.03.004.
[53]. Ma Y, Wang J, Gao J, et al. Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury. Thromb Haemost 2015;113:338–349. doi:10.1160/TH14-04-0360.
[54]. Kambara T, Shibata R, Ohashi K, et al. C1q/tumor necrosis factor-related protein 9 protects against acute myocardial injury through an adiponectin receptor I-AMPK-dependent mechanism. Mol Cell Biol 2015;35:2173–2185. doi:10.1128/MCB.01518-14.
[55]. Wang HW, Liu HJ, Cao H, et al. Diosgenin protects rats from myocardial inflammatory injury induced by ischemia-reperfusion. Med Sci Monit 2018;24:246–253. doi:10.12659/msm.907745.
[56]. Wang DX, Huang Z, Li QJ, et al. Involvement of HSP90 in ischemic postconditioning-induced cardioprotection by inhibition of the complement system, JNK and inflammation. Acta Cir Bras 2020;35:e202000105. doi:10.1590/s0102-865020200010000005.
[57]. Xi J, Li QQ, Li BQ, et al. miR-155 inhibition represents a potential valuable regulator in mitigating myocardial hypoxia/reoxygenation injury through targeting BAG5 and MAPK/JNK signaling. Mol Med Rep 2020;21:1011–1020. doi:10.3892/mmr.2020.10924.
[58]. Liu S, He Y, Shi J, et al. Allicin attenuates myocardial ischemia reperfusion injury in rats by inhibition of inflammation and oxidative stress. Transplant Proc 2019;51:2060–2065. doi:10.1016/j.transproceed.2019.04.039.
[59]. Zhang F, Shi D, Wang X, et al. β-cryptoxanthin alleviates myocardial ischaemia/reperfusion injury by inhibiting NF-κB-mediated inflammatory signalling in rats. Arch Physiol Biochem 2020;1–8. doi:10.1080/13813455.2020.1760302.
[60]. Li W, Li Y, Chu Y, et al. PLCE1 promotes myocardial ischemia-reperfusion injury in H/R H9c2 cells and I/R rats by promoting inflammation. Biosci Rep 2019;39. doi:10.1042/BSR20181613.
[61]. Zhang X, Wang Y, Shen W, et al. Rosa rugosa flavonoids alleviate myocardial ischemia reperfusion injury in mice by suppressing JNK and p38 MAPK. Microcirculation 2017;24. doi:10.1111/micc.12385.
[62]. Zhang H, Zhu T, Liu W, et al. TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses in myocardial ischemia/reperfusion injury. J Mol Med (Berl) 2015;93:1033–1043. doi:10.1007/s00109-015-1288-9.
[63]. Suchal K, Malik S, Gamad N, et al. Kaempferol attenuates myocardial ischemic injury via inhibition of MAPK signaling pathway in experimental model of myocardial ischemia-reperfusion injury. Oxid Med Cell Longev 2016;2016:7580731. doi:10.1155/2016/7580731.
[64]. Liu X, Zhang L, Qin H, et al. Inhibition of TRAF3 expression alleviates cardiac ischemia reperfusion (IR) injury: a mechanism involving in apoptosis, inflammation and oxidative stress. Biochem Biophys Res Commun 2018;506:298–305. doi:10.1016/j.bbrc.2018.10.058.
[65]. Dong LY, Qiu XX, Zhuang Y, et al. Y-27632, a Rho-kinase inhibitor, attenuates myocardial ischemia-reperfusion injury in rats. Int J Mol Med 2019;43:1911–1919. doi:10.3892/ijmm.2019.4097.
[66]. Qian X, Zhu M, Qian W, et al. Vitamin D attenuates myocardial ischemia-reperfusion injury by inhibiting inflammation via suppressing the RhoA/ROCK/NF-κB pathway. Biotechnol Appl Biochem 2019;66:850–857. doi:10.1002/bab.1797.
[67]. Suchal K, Malik S, Khan SI, et al. Molecular pathways involved in the Amelioration of myocardial injury in diabetic rats by Kaempferol. Int J Mol Sci 2017;18. doi:10.3390/ijms18051001.
[68]. Suchal K, Malik S, Khan SI, et al. Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: role of AGE-RAGE/MAPK pathways. Sci Rep 2017;7:42027. doi:10.1038/srep42027.
[69]. Yang J, Fan Z, Yang J, et al. microRNA-22 attenuates myocardial ischemia-reperfusion injury via an anti-inflammatory mechanism in rats. Exp Ther Med 2016;12:3249–3255. doi:10.3892/etm.2016.3777.
[70]. Erikson JM, Valente AJ, Mummidi S, et al. Targeting TRAF3IP2 by genetic and interventional approaches inhibits ischemia/reperfusion-induced myocardial injury and adverse remodeling. J Biol Chem 2017;292:2345–2358. doi:10.1074/jbc.M116.764522.
[71]. Jiang T, You H, You D, et al. A miR-1275 mimic protects myocardiocyte apoptosis by regulating the Wnt/NF-κB pathway in a rat model of myocardial ischemia-reperfusion-induced myocardial injury. Mol Cell Biochem 2020;466:129–137. doi:10.1007/s11010-020-03695-w.
[72]. Nakamura K, Sano S, Fuster JJ, et al. Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/reperfusion injury. J Biol Chem 2016;291:2566–2575. doi:10.1074/jbc.M115.693937.
[73]. Adamek A, Jung S, Dienesch C, et al. Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice. Eur J Pharmacol 2007;571:51–54. doi:10.1016/j.ejphar.2007.05.040.
[74]. Sánchez-Galán E, Gómez-Hernández A, Vidal C, et al. Leukotriene B4 enhances the activity of nuclear factor-kappaB pathway through BLT1 and BLT2 receptors in atherosclerosis. Cardiovasc Res 2009;81:216–225. doi:10.1093/cvr/cvn277.
[75]. Elshazly SM, Abd El Motteleb DM, Nassar NN. The selective 5-LOX inhibitor 11-keto-β-boswellic acid protects against myocardial ischemia reperfusion injury in rats: involvement of redox and inflammatory cascades. Naunyn Schmiedebergs Arch Pharmacol 2013;386:823–833. doi:10.1007/s00210-013-0885-9.
[76]. de Hoog VC, Bovens SM, de Jager SC, et al. BLT1 antagonist LSN2792613 reduces infarct size in a mouse model of myocardial ischaemia-reperfusion injury. Cardiovasc Res 2015;108:367–376. doi:10.1093/cvr/cvv224.
[77]. Liu Z, Tao B, Fan S, et al. MicroRNA-145 protects against myocardial ischemia reperfusion injury via CaMKII-mediated antiapoptotic and anti-inflammatory pathways. Oxid Med Cell Longev 2019;2019:8948657. doi:10.1155/2019/8948657.
[78]. Clark EA. A short history of the B-cell-associated surface molecule CD40. Front Immunol 2014;5:472. doi:10.3389/fimmu.2014.00472.
[79]. Jansen MF, Hollander MR, van Royen N, et al. CD40 in coronary artery disease: a matter of macrophages. Basic Res Cardiol 2016;111:38. doi:10.1007/s00395-016-0554-5.
[80]. Zhang R, Han D, Li Z, et al. Ginkgolide C alleviates myocardial ischemia/reperfusion-induced inflammatory injury via inhibition of CD40-NF-κB pathway. Front Pharmacol 2018;9:109. doi:10.3389/fphar.2018.00109.
[81]. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655–1657. doi:10.1126/science.296.5573.1655.
[82]. Fujio Y, Nguyen T, Wencker D, et al. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 2000;101:660–667. doi:10.1161/01.cir.101.6.660.
[83]. Lv ZQ, Yang CY, Xing QS. TRIM59 attenuates inflammation and apoptosis caused by myocardial ischemia reperfusion injury by activating the PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 2020;24:5192. doi:10.26355/eurrev_202005_21296.
[84]. Wang S, Zhao Y, Song J, et al. Total flavonoids from Anchusa italica Retz. Improve cardiac function and attenuate cardiac remodeling post myocardial infarction in mice. J Ethnopharmacol 2020;257:112887. doi:10.1016/j.jep.2020.112887.
[85]. Xin G, Xu-Yong L, Shan H, et al. SH2B1 protects cardiomyocytes from ischemia/reperfusion injury via the activation of the PI3K/AKT pathway. Int Immunopharmacol 2020;83:105910. doi:10.1016/j.intimp.2019.105910.
[86]. Alyahya AM, Al-Masri A, Hersi A, et al. The effects of progranulin in a rat model of acute myocardial ischemia/reperfusion are mediated by activation of the P13K/Akt signaling pathway. Med Sci Monit Basic Res 2019;25:229–237. doi:10.12659/MSMBR.916258.
[87]. Qin CY, Zhang HW, Gu J, et al. Mitochondrial DNA-induced inflammatory damage contributes to myocardial ischemia reperfusion injury in rats: cardioprotective role of epigallocatechin. Mol Med Rep 2017;16:7569–7576. doi:10.3892/mmr.2017.7515.
[88]. Yu H, Zhang H, Zhao W, et al. Gypenoside protects against myocardial ischemia-reperfusion injury by inhibiting cardiomyocytes apoptosis via inhibition of CHOP pathway and activation of PI3K/Akt pathway in vivo and in vitro. Cell Physiol Biochem 2016;39:123–136. doi:10.1159/000445611.
[89]. Wang L, Ma H, Xue Y, et al. Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase and nuclear factor-κB signaling pathways. Exp Ther Med 2018;15:1225–1232. doi:10.3892/etm.2017.5575.
[90]. Luan Y, Sun C, Wang J, et al. Baicalin attenuates myocardial ischemia-reperfusion injury through Akt/NF-κB pathway. J Cell Biochem 2019;120:3212–3219. doi:10.1002/jcb.27587.
[91]. Xu T, Qin G, Jiang W, et al. 6-Gingerol protects heart by suppressing myocardial ischemia/reperfusion induced inflammation via the PI3K/Akt-dependent mechanism in rats. Evid Based Complement Alternat Med 2018;2018:6209679. doi:10.1155/2018/6209679.
[92]. Barlaka E, Galatou E, Mellidis K, et al. Role of pleiotropic properties of peroxisome proliferator-activated receptors in the heart: focus on the nonmetabolic effects in cardiac protection. Cardiovasc Ther 2016;34:37–48. doi:10.1111/1755-5922.12166.
[93]. Liu X, Yu Z, Huang X, et al. Peroxisome proliferator-activated receptor (γPPARγ) mediates the protective effect of quercetin against myocardial ischemia-reperfusion injury via suppressing the NF-κB pathway. Am J Transl Res 2016;8:5169–5186.
[94]. Han J, Wang D, Ye L, et al. Rosmarinic acid protects against inflammation and cardiomyocyte apoptosis during myocardial ischemia/reperfusion injury by activating peroxisome proliferator-activated receptor gamma. Front Pharmacol 2017;8:456. doi:10.3389/fphar.2017.00456.
[95]. Nakano Y, Matoba T, Tokutome M, et al. Nanoparticle-mediated delivery of irbesartan induces cardioprotection from myocardial ischemia-reperfusion injury by antagonizing monocyte-mediated inflammation. Sci Rep 2016;6:29601. doi:10.1038/srep29601.
[96]. Yuasa D, Ohashi K, Shibata R, et al. C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart. FASEB J 2016;30:1065–1075. doi:10.1096/fj.15-279885.
[97]. Winnik S, Auwerx J, Sinclair DA, et al. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J 2015;36:3404–3412. doi:10.1093/eurheartj/ehv290.
[98]. Yu L, Li Q, Yu B, et al. Berberine attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation response: role of silent information regulator 1. Oxid Med Cell Longev 2016;2016:1689602. doi:10.1155/2016/1689602.
[99]. Marchetti C, Chojnacki J, Toldo S, et al. A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse. J Cardiovasc Pharmacol 2014;63:316–322. doi:10.1097/FJC.0000000000000053.
[100]. Toldo S, Mauro AG, Cutter Z, et al. The NLRP3 inflammasome inhibitor, OLT1177 (Dapansutrile), reduces infarct size and preserves contractile function after ischemia reperfusion injury in the mouse. J Cardiovasc Pharmacol 2019;73:215–222. doi:10.1097/FJC.0000000000000658.
[101]. Zhou T, Xiang DK, Li SN, et al. MicroRNA-495 ameliorates cardiac microvascular endothelial cell injury and inflammatory reaction by suppressing the NLRP3 inflammasome signaling pathway. Cell Physiol Biochem 2018;49:798–815. doi:10.1159/000493042.
[102]. Liang H, Li F, Li H, et al. Overexpression of lncRNA HULC attenuates myocardial ischemia/reperfusion injury in rat models and apoptosis of hypoxia/reoxygenation cardiomyocytes via targeting miR-377-5p through NLRP3/Caspase-1/IL-1β signaling pathway inhibition. Immunol Invest 2021;50:925–938. doi:10.1080/08820139.2020.1791178.
[103]. Xiao B, Huang X, Wang Q, et al. Beta-Asarone alleviates myocardial ischemia-reperfusion injury by inhibiting inflammatory response and NLRP3 inflammasome mediated pyroptosis. Biol Pharm Bull 2020;43:1046–1051. doi:10.1248/bpb.b19-00926.
[104]. Sun W, Lu H, Lyu L, et al. Gastrodin ameliorates microvascular reperfusion injury-induced pyroptosis by regulating the NLRP3/caspase-1 pathway. J Physiol Biochem 2019;75:531–547. doi:10.1007/s13105-019-00702-7.
[105]. Toldo S, Mezzaroma E, McGeough MD, et al. Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart. Cardiovasc Res 2015;105:203–212. doi:10.1093/cvr/cvu259.
[106]. Qiu Z, He Y, Ming H, et al. Lipopolysaccharide (LPS) aggravates high glucose- and hypoxia/reoxygenation-induced injury through activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. J Diabetes Res 2019;2019:8151836. doi:10.1155/2019/8151836.
[107]. Bai Y, Li Z, Liu W, et al. Biochanin A attenuates myocardial ischemia/reperfusion injury through the TLR4/NF-κB/NLRP3 signaling pathway. Acta Cir Bras 2019;34:e201901104. doi:10.1590/s0102-865020190110000004.
[108]. Wu Y, Zhang Y, Zhang J, et al. Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2X(7)R/NLRP3 inflammasome. J Mol Cell Cardiol 2020;139:75–86. doi:10.1016/j.yjmcc.2019.12.011.
[109]. Shen-Orr SS, Furman D, Kidd BA, et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst 2016;3. 374–384.e4. doi:10.1016/j.cels.2016.09.009.
[110]. Kim HC, Kim E, Bae JI, et al. Sevoflurane postconditioning reduces apoptosis by activating the JAK-STAT pathway after transient global cerebral ischemia in rats. J Neurosurg Anesthesiol 2017;29:37–45. doi:10.1097/ANA.0000000000000331.
[111]. De S, Manna A, Kundu S, et al. Allylpyrocatechol attenuates collagen-induced arthritis via attenuation of oxidative stress secondary to modulation of the MAPK, JAK/STAT, and Nrf2/HO-1 pathways. J Pharmacol Exp Ther 2017;360:249–259. doi:10.1124/jpet.116.238444.
[112]. Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trends Biochem Sci 2000;25:496–502. doi:10.1016/s0968-0004(00)01624-8.
[113]. Gross ER, Hsu AK, Gross GJ. The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3 beta. Am J Physiol Heart Circ Physiol 2006;291:H827–834. doi:10.1152/ajpheart.00003.2006.
[114]. Li J, Xiang X, Gong X, et al. Cilostazol protects mice against myocardium ischemic/reperfusion injury by activating a PPARγ/JAK2/STAT3 pathway. Biomed Pharmacother 2017;94:995–1001. doi:10.1016/j.biopha.2017.07.143.
[115]. Billah M, Ridiandries A, Rayner BS, et al. Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection. Basic Res Cardiol 2019;115:3. doi:10.1007/s00395-019-0763-9.
[116]. Li D, Lu N, Han J, et al. Eriodictyol attenuates myocardial ischemia-reperfusion injury through the activation of JAK2. Front Pharmacol 2018;9:33. doi:10.3389/fphar.2018.00033.
[117]. Yin Q, Zhao B, Zhu J, et al. JLX001 improves myocardial ischemia-reperfusion injury by activating Jak2-Stat3 pathway. Life Sci 2020;257:118083. doi:10.1016/j.lfs.2020.118083.
[118]. Liu S, Yang Y, Song YQ, et al. Protective effects of N(2)-L-alanyl-L-glutamine mediated by the JAK2/STAT3 signaling pathway on myocardial ischemia reperfusion. Mol Med Rep 2018;17:5102–5108. doi:10.3892/mmr.2018.8543.
[119]. Zhao C, Zhang B, Jiang J, et al. Up-regulation of ANXA1 suppresses polymorphonuclear neutrophil infiltration and myeloperoxidase activity by activating STAT3 signaling pathway in rat models of myocardial ischemia-reperfusion injury. Cell Signal 2019;62:109325. doi:10.1016/j.cellsig.2019.05.010.
[120]. Wang S, He F, Li Z, et al. YB1 protects cardiac myocytes against H2O2-induced injury via suppression of PIAS3 mRNA and phosphorylation of STAT3. Mol Med Rep 2019;19:4579–4588. doi:10.3892/mmr.2019.10119.
[121]. Liao Y, Hu X, Guo X, et al. Promoting effects of IL-23 on myocardial ischemia and reperfusion are associated with increased expression of IL-17A and upregulation of the JAK2-STAT3 signaling pathway. Mol Med Rep 2017;16:9309–9316. doi:10.3892/mmr.2017.7771.
[122]. Mathur AN, Chang HC, Zisoulis DG, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 2007;178:4901–4907. doi:10.4049/jimmunol.178.8.4901.
[123]. Liao YH, Xia N, Zhou SF, et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 2012;59:420–429. doi:10.1016/j.jacc.2011.10.863.
[124]. Guo LL, Guo ML, Yao J, et al. MicroRNA-421 improves ischemia/reperfusion injury via regulation toll-like receptor 4 pathway. J Int Med Res 2020;48:300060519871863. doi:10.1177/0300060519871863.
[125]. Xu M, Li X, Song L. Baicalin regulates macrophages polarization and alleviates myocardial ischaemia/reperfusion injury via inhibiting JAK/STAT pathway. Pharm Biol 2020;58:655–663. doi:10.1080/13880209.2020.1779318.
[126]. Wang EW, Han YY, Jia XS. PAFR-deficiency alleviates myocardial ischemia/reperfusion injury in mice via suppressing inflammation, oxidative stress and apoptosis. Biochem Biophys Res Commun 2018;495:2475–2481. doi:10.1016/j.bbrc.2017.12.132.
[127]. Song N, Ma J, Meng XW, et al. Heat shock protein 70 protects the heart from ischemia/reperfusion injury through inhibition of p38 MAPK signaling. Oxid Med Cell Longev 2020;2020:3908641. doi:10.1155/2020/3908641.
[128]. Singh N, Ahmad Z, Baid N, et al. Host heme oxygenase-1: friend or foe in tackling pathogens. IUBMB Life 2018;70:869–880. doi:10.1002/iub.1868.
[129]. Otterbein LE, Foresti R, Motterlini R. Heme oxygenase-1 and carbon monoxide in the heart: the balancing act between danger signaling and pro-survival. Circ Res 2016;118:1940–1959. doi:10.1161/CIRCRESAHA.116.306588.
[130]. Hinkel R, Lange P, Petersen B, et al. Heme oxygenase-1 gene therapy provides cardioprotection via control of post-ischemic inflammation: an experimental study in a pre-clinical pig model. J Am Coll Cardiol 2015;66:154–165. doi:10.1016/j.jacc.2015.04.064.
[131]. Ndisang JF. Synergistic interaction between heme oxygenase (HO) and nuclear-factor E2-related factor-2 (Nrf2) against oxidative stress in cardiovascular related diseases. Curr Pharm Des 2017;23:1465–1470. doi:10.2174/1381612823666170113153818.
[132]. Cheng L, Jin Z, Zhao R, et al. Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med 2015;8:10420–10428.
[133]. Xue M, Momiji H, Rabbani N, et al. Frequency modulated translocational oscillations of Nrf2 mediate the antioxidant response element cytoprotective transcriptional response. Antioxid Redox Signal 2015;23:613–629. doi:10.1089/ars.2014.5962.
[134]. Zhang X, Xiao Z, Yao J, et al. Participation of protein kinase C in the activation of Nrf2 signaling by ischemic preconditioning in the isolated rabbit heart. Mol Cell Biochem 2013;372:169–179. doi:10.1007/s11010-012-1458-9.
[135]. Yang M, Mao G, Ouyang L, et al. Crocetin alleviates myocardial ischemia/reperfusion injury by regulating inflammation and the unfolded protein response. Mol Med Rep 2020;21:641–648. doi:10.3892/mmr.2019.10891.
[136]. Yu H, Shi L, Zhao S, et al. Triptolide attenuates myocardial ischemia/reperfusion injuries in rats by inducing the activation of Nrf2/HO-1 defense pathway. Cardiovasc Toxicol 2016;16:325–335. doi:10.1007/s12012-015-9342-y.
[137]. Reforgiato MR, Milano G, Fabriàs G, et al. Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury. Basic Res Cardiol 2016;111:12. doi:10.1007/s00395-016-0533-x.
[138]. Yang P, Zhou Y, Xia Q, et al. Astragaloside IV regulates the PI3K/Akt/HO-1 signaling pathway and inhibits H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation. Biol Pharm Bull 2019;42:721–727. doi:10.1248/bpb.b18-00854.
[139]. Chen XJ, Ren SM, Dong JZ, et al. Ginkgo biloba extract-761 protects myocardium by regulating Akt/Nrf2 signal pathway. Drug Des Devel Ther 2019;13:647–655. doi:10.2147/DDDT.S191537.
[140]. Chen T, Mou Y, Tan J, et al. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 2015;25:55–64. doi:10.1016/j.intimp.2015.01.011.
[141]. Liu K, Wang F, Wang S, et al. Mangiferin attenuates myocardial ischemia-reperfusion injury via MAPK/Nrf-2/HO-1/NF-κB in vitro and in vivo. Oxid Med Cell Longev 2019;2019:7285434. doi:10.1155/2019/7285434.
[142]. Chen M, Wang M, Yang Q, et al. Antioxidant effects of hydroxysafflor yellow A and acetyl-11-keto-β-boswellic acid in combination on isoproterenol-induced myocardial injury in rats. Int J Mol Med 2016;37:1501–1510. doi:10.3892/ijmm.2016.2571.
[143]. Zhi W, Li K, Wang H, et al. Melatonin elicits protective effects on OGD/R-insulted H9c2 cells by activating PGC-1α/Nrf2 signaling. Int J Mol Med 2020;45:1294–1304. doi:10.3892/ijmm.2020.4514.

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

Copyright © 2022 China Heart House.