• angiogenesis
• fibroblasts
• fibrosis
• infarction
• inflammation
• macrophages

• Humans
• Myocardial Infarction/metabolism
• Myocardial Infarction/pathology
• Animals
• Signal Transduction
• Regeneration
• Inflammation Mediators/metabolism
• Myocardium/metabolism
• Myocardium/pathology

• R01 HL076246 NHLBI NIH HHS
• R01 HL085440 NHLBI NIH HHS
• R01 HL149407 NHLBI NIH HHS

Background: Myocardial ischemia/reperfusion (I/R) injury is associated with multiple serious clinical manifestations. Autophagy is upregulated in a short period of ischemia and further enhanced during reperfusion phase, which was considered as a “double-edged sword” in the pathological process of myocardial I/R injury. In addition, NLRP3 inflammasome triggers myocardial inflammatory response, which leads to cardiomyocyte death via pyroptosis and promotes subsequent myocardial remodelling. Qishen Yiqi Dripping Pill (QSYQ) has been recognized as a potential protective agent of cardiovascular diseases.

Objective: We predicted the bioactive compounds, targets and pathways of OSYQ intervening on myocardial I/R injury by network pharmacology. Furthermore, we investigated the effect of QSYQ on myocardial I/R injury and explored its underlying mechanism via autophagy and NLRP3 Inflammasome.

Methods: Bioactive compounds, targets of QSYQ and relevant targets of myocardial I/R injury were collected from public databases. The protein-protein interaction network, Gene ontology and KEGG pathway enrichment analysis were carried out to screen the key compounds, target genes, functional annotation and pivotal pathways. Molecular docking was used to validate the binding association between target genes and key bioactive ingredients. Furthermore, sixty SD rats were randomized into four groups: 1) sham, 2) model, 3) captopril and 4) QSYQ pretreatment (14 days before and after surgery). Each arm was subjected to ischemia/reperfusion surgery except sham arm (30 min coronary ligation, then reperfusion). Left ventricular (LV) function were evaluated and the hearts were used to evaluate size of myocardial infarction, cardiomyocyte fibrosis, and myocardial autophagosomes.

Results: The network pharmacology revealed the mechanism of QSYQ intervening on myocardial I/R injury might be related to NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, autophagy-animal, etc., Molecular-docking suggested the core target proteins had good binding association with bioactive compounds of QSYQ. The experiment confirmed that QSYQ attenuated myocardial infarct size, decreased inflammatory infiltration and collagen fiber deposition and alleviated the autophagosome and myocardium ultrastructure injury, leading to LV systolic function improvement. The possible mechanism of cardioprotection was due to regulating autophagy-related proteins, activating PI3K/Akt-mTOR signaling pathway, and inhibiting activation and assembly of NLRP3 inflammasome.

Conclusion: QSYQ ameliorated myocardial I/R injury via suppressing excessive autophagy and NLRP3 Inflammasome.

• China Postdoctoral Science Foundation

• Cardioprotection
• Co-morbidities
• Diabetes
• Inflammation
• Microvascular injury
• Remote conditioning

• Animals
• Humans
• Ischemic Preconditioning, Myocardial
• Myocardial Infarction/pathology
• Myocardial Reperfusion Injury/pathology
• Reproducibility of Results
• Risk Factors

• Biomarkers
• Cardiovascular diseases
• Myocardial infarction
• Pathophysiology
• Toll-like receptors

• Cytokines
• Heart Failure
• Humans
• Myocardial Infarction/therapy
• Myocarditis
• Receptors, Pattern Recognition
• Toll-Like Receptors

• Poly(I:C)
• autophagy
• cardio-protection
• ischemia/reperfusion injury

• MCPIP-1
• inflammation
• ischemic inflammation
• resolution
• viral infection

Emerging evidence suggests that Toll-like receptors (TLRs) ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion (I/R) injury. As the ligand of TLR3, polyinosinic-polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA, whether its preconditioning can exhibit a cardioprotective phenotype remains unknown. Here, we report the protective effect of poly(I:C) pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway. Poly(I:C) pretreatment leads to a significant reduction of infarct size, improvement of cardiac function, and downregulation of inflammatory cytokines and apoptotic molecules compared with controls. Subsequently, our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced, and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C) pretreatment, while knock out of TLR3 suppresses the cardioprotection of poly(I:C) preconditioning through a decreased activation of PI3K/Akt signaling. Moreover, inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C) preconditioning-induced cardioprotective effect. In conclusion, our results reveal that poly(I:C) preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3, and the downstream PI3K/Akt signaling, which may provide a potential pharmacologic target for perioperative cardioprotection.

• ST-segment elevation myocardial infraction
• anakinra
• colchicine
• ischemia reperfusion injury
• mitochondrial pathways
• myocardial injury
• oxidative stress
• platelets
• revacept
• tocilizumab

• AMI, acute myocardial infarction
• CARD, caspase activation and recruitment domain
• CVD, cardiovascular disease
• Ca2+, calcium ion
• DAMPs, danger-associated molecular patterns
• DAP, D-glutamyl-meso-diaminopimelic acid
• ER, endoplasmic reticulum
• HF, heart failure
• I/R, ischemia/reperfusion
• IL, interleukin
• MAPK, mitogen-activated protein kinase
• NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells
• NLR, nucleotide-binding oligomerization domain-like receptors
• NLRP, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor
• NLRP3
• NOD, Nucleotide-binding oligomerization domain-containing protein
• NOD1
• PAMP, pathogen-associated molecular pattern
• ROS, reactive oxygen species
• SR, sarcoplasmic reticulum
• TLR, toll-like receptor
• cardiovascular disease
• innate immune system
• nucleotide-binding oligomerization domain-like receptors
• toll-like receptors

• Cardioprotection
• Inflammasome
• Innate immunity
• Ischaemia
• Reperfusion

Toll-like receptor 2 (TLR2)-mediated myocardial inflammation serves an important role in promoting myocardial ischemic/reperfusion (I/R) injury. Previous studies have shown that miR-499 is critical for cardioprotection after ischemic postconditioning (IPostC). Therefore, the present study evaluated the protective effect of IPostC on the myocardium by inhibiting TLR2, and also assessed the involvement of microRNA (miR)-499. Rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The IPostC was 3 cycles of 30 sec of reperfusion and 30 sec of re-occlusion prior to reperfusion. In total, 90 rats were randomly divided into six groups (n=15 per group): Sham; I/R; IPostC; miR-499 negative control adeno-associated virus (AAV) vectors + IPostC; miR-499 inhibitor AAV vectors + IPostC; and miR-499 mimic AAV vectors + IPostC. It was identified that IPostC significantly decreased the I/R-induced cardiomyocyte apoptotic index (29.4±2.03% in IPostC vs. 42.64±2.27% in I/R; P<0.05) and myocardial infarct size (48.53±2.49% in IPostC vs. 66.52±3.1% in I/R; P<0.05). Moreover, these beneficial effects were accompanied by increased miR-499 expression levels (as demonstrated by reverse transcription-quantitative PCR) in the myocardial tissue and decreased TLR2, protein kinase C (PKC), interleukin (IL)-1β and IL-6 expression levels (as demonstrated by western blotting and ELISA) in the myocardium and serum. The results indicated that IPostC + miR-499 mimics significantly inhibited inflammation and the PKC signaling pathway and enhanced the anti-inflammatory and anti-apoptotic effects of IPostC. However, IPostC + miR-499 inhibitors had the opposite effect. Therefore, it was speculated that IPostC may have a miR-499-dependent cardioprotective effect. The present results suggested that miR-499 may be involved in IPostC-mediated ischemic cardioprotection, which may occur via local and systemic TLR2 inhibition, subsequent inhibition of the PKC signaling pathway and a decrease in inflammatory cytokine release, including IL-1β and IL-6. Moreover, these effects will ultimately lead to a decrease in the myocardial apoptotic index and myocardial infarct size via the induction of the anti-apoptotic protein Bcl-2, and inhibition of the pro-apoptotic protein Bax in myocardium.

Our understanding of platelet function has traditionally focused on their roles in physiological hemostasis and pathological thrombosis, with the latter being causative of vessel occlusion and subsequent ischemic damage to various tissues. In particular, numerous in vivo studies have implicated causative roles for platelets in the pathogenesis of ischemia-reperfusion (I/R) injury to the myocardium. However, platelets clearly have more complex pathophysiological roles, particularly as a result of the heterogeneous nature of biologically active cargo secreted from their granules or contained within released microparticles or exosomes. While some of these released mediators amplify platelet activation and thrombosis through autocrine or paracrine amplification pathways, they can also regulate diverse cellular functions within the localized microenvironment and recruit progenitor cells to the damage site to facilitate repair processes. Notably, there is evidence to support cardioprotective roles for platelet mediators during I/R injury. As such, it is becoming more widely appreciated that platelets fulfill a host of physiological and pathological roles beyond our basic understanding. Therefore, the purpose of this perspective is to consider whether platelets, through their released mediators, can assume a paradoxically beneficial role to promote cardiac recovery after I/R injury.

• cardiac recovery
• myocardial infarction
• platelets
• secretion

• Innate immune

• cardiac muscle
• cardiomyocyte
• cryoinjury
• leucocytes
• non-mammalian animal model
• thoracotomy

• chemokines
• cytokines
• fibrosis
• immune cells
• inflammation
• myocardial infarction
• myocytes, cardiac

• ASC
• Acute coronary syndrome
• Heart
• Inflammasome
• Inflammation
• Ischemia-reperfusion
• NLRP3
• Revascularization

• Animals
• Carrier Proteins/immunology
• Cytokines/immunology
• Female
• Immunity, Innate/immunology
• Inflammasomes/immunology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Reperfusion Injury/immunology
• Myocardial Reperfusion Injury/pathology
• NLR Family, Pyrin Domain-Containing 3 Protein

• cardioprotection
• exosomes
• heat shock protein
• ischemia-reperfusion injury
• toll-like receptor

• Cross talk
• PI3K/AKT
• Signaling
• TLRs

• Cross talk
• PI3K/AKT
• Signaling
• TLRs

Recent data have indicated that the myocardium may act as an immune organ initiating cardiac innate immune response and inflammation. It has been suggested that activation of the immune system occurs upon the interaction of damage-associated molecular patterns (DAMPs) generated and released during ischemic damage with pattern recognition receptors (Toll like receptors; TLR) present in cardiac cells. Among TLRs, TLR4, and TLR2 are the ones mostly expressed in cardiac tissue. Whereas TLR4 has shown to play a detrimental role in myocardial ischemia/reperfusion (I/R) injury, the effect elicited by TLR2 activation remains controversial. Once activated, TLR signaling may occur via the Myd88- and Trif- dependent pathways leading to NFκB and IFN-3 activation, respectively, and subsequent stimulation of pro-inflammatory and immunomodulatory cytokine gene expression. Cytokine release contributes to neutrophils activation, recruitment, adhesion and infiltration to the site of cardiac injury further perpetuating the inflammatory process. This mini-review will focus on the current knowledge regarding the role of the heart in inducing and coordinating the innate inflammatory response via the TLR signaling pathway in myocardial I/R injury.

• cytokines
• inflammation
• innate immune response
• ischemia/reperfusion injury
• myocardium
• toll-like receptor

Heart failure (HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors (TLRs) and nod-like receptors (NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.

• Heart failure
• Innate immune system
• Toll-like receptors
• Inflammation

The development of techniques for genomics study makes it possible for us to further our knowledge about the physiopathology of various immunological or infectious diseases. These techniques improve our understanding of the development and evolution of such diseases, including those of cardiovascular origin, whilst they help to bring about the design of new therapeutic strategies. We are reviewing the genetic alterations of immunity in said field, and focusing on the signaling pathway of toll-like receptors because not only does this play a decisive role in response to microorganisms, it is also heavily involved in modulating the inflammatory response to tissue damage, a side effect of numerous cardiovascular diseases. These alterations in tissue homeostasis are present under a wide range of circumstances, such as reperfusion ischemia (myocardial infarction) phenomena, arteriosclerosis, or valvulopathy.

• genome-wide association study
• innate immune system
• ischemic/reperfusion
• myocardial infarction
• single-nucleotide polymorphism

Recent studies indicate that the innate immune system is not only triggered by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As triggers for the innate immune NLRP3 inflammasome protein complex appear to overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NLRP3 inflammasome is involved in IPC and acute I/R injury of the heart.

Baseline cardiac performance and acute I/R injury were investigated in isolated, Langendorff-perfused hearts from wild-type (WT), ASC^−/− and NLRP3^−/− mice. Deletion of NLRP3 inflammasome components ASC^−/− or NLRP3^−/− did not affect baseline performance. The deletions exacerbated I/R-induced mechanical dysfunction, but were without effect on I/R-induced cell death. When subjected to IPC, WT and ASC^−/− hearts were protected against I/R injury (improved function and less cell death). However, IPC did not protect NLRP3^−/− hearts against I/R injury. NLRP3^−/− hearts had significantly decreased cardiac IL-6 levels with a trend towards lower IL-1β levels at end reperfusion, suggesting abrogation of IPC through diminished IL-6 and/or IL-1β signaling. Subsequent experiments showed that neutralising IL-6 using an antibody against IL-6 abrogated IPC in WT hearts. However, inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) did not abrogate IPC in WT hearts. Analysis of survival kinases after IPC demonstrated decreased STAT3 expression in NLRP3^−/− hearts when compared to WT hearts.

The data suggest that the innate immune NLRP3 protein, in an NLRP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6/STAT3 dependent mechanism.

• Animals
• Carrier Proteins/genetics
• Carrier Proteins/immunology
• Gene Deletion
• Immunity, Innate/genetics
• Inflammasomes/genetics
• Inflammasomes/immunology
• Interleukin-1beta/genetics
• Interleukin-1beta/immunology
• Interleukin-6/genetics
• Interleukin-6/immunology
• Ischemic Preconditioning, Myocardial
• Mice
• Mice, Knockout
• Myocardium/immunology
• NLR Family, Pyrin Domain-Containing 3 Protein
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/immunology
• Signal Transduction/genetics
• Signal Transduction/immunology

• Animals
• Disease Models, Animal
• Immunity, Innate/immunology
• Kidney/metabolism
• Kidney/pathology
• Myocardial Infarction/immunology
• Myocardium/metabolism
• Myocardium/pathology
• Organ Transplantation
• Reperfusion Injury/immunology
• Toll-Like Receptor 2/immunology
• Toll-Like Receptor 4/immunology