Search

Ischemic heart disease is caused by coronary artery occlusion. Despite the increasing number and success of interventions for restoring coronary artery perfusion, myocardial ischemia–reperfusion (I/R) injury remains a significant cause of morbidity and mortality worldwide. Inspired by the impact of I/R on the Cx43 trafficking to the intercalated discs (ICDs), we aim to explore the potential mechanisms underlying the downregulation of Cx43 in ICDs after myocardial I/R. Gene set enrichment analysis (GSEA), Western blotting, and immunofluorescence experiments showed that Myocardial I/R activated the P38MAPK signaling pathway and promoted microtubule depolymerization. Inhibition of P38MAPK signaling pathway activation attenuated I/R-induced microtubule depolymerization. The ability of SB203580 to recover the distribution of Cx43 and electrophysiological parameters in I/R myocardium depended on microtubule stability. Our study suggests that microtubule depolymerization caused by the activation of the P38MAPK signaling pathway is an important mechanism underlying the downregulation of Cx43 in ICDs after myocardial I/R. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of death from cardiovascular disease in humans, especially in individuals exposed to cold environments. Long non-coding RNAs (lncRNAs) regulate MIRI through multiple mechanisms.This study explored the regulatory effect of lncRNA-AK138945 on myocardial ischemia-reperfusion injury and its mechanism.

Hederagenin (HDG), a medical herb, is known for its beneficial activities against diverse diseases. The cardioprotective effect of HDG has been preliminarily disclosed, but the efficacy and underlying mechanism by which HDG protects against myocardial ischemia–reperfusion (MI/R) injury have not been elucidated yet. To simulate MI/R injury, the left anterior descending artery was occluded for 30 min and then reperfusion for 120 min in a rat model, and the cellular model of hypoxia–reoxygenation (H/R) injury was constructed in H9c2 cardiomyocytes. Hematoxylin–eosin, Prussian blue, and 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) staining were conducted to assess the histological injury, iron deposition, and myocardial infarction. Myocardial enzymes and oxidative stress-related factors were detected using their commercial kits. Lipid peroxidation was measured using BODIPY581/591 probe, and iron content was detected. Cell counting kit (CCK)-8, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and flow cytometry assays were performed to assess cell viability and apoptosis. Protein levels were investigated by western blot. The interaction between HDG and 5-lipoxygenase (ALOX5) was verified using molecular docking. Our findings indicated that HDG significantly attenuated myocardial dysfunction by reducing infarction and myocardial injury. HDG significantly attenuated myocardial apoptosis in vitro and in vivo, as well as alleviating oxidative stress via reducing reactive oxygen species (ROS) and maintaining the balance between antioxidant and oxidant enzymes. Meanwhile, HDG inhibited I/R-induced ferroptosis in myocardium and cardiomyocytes, including reducing lipid peroxidation and iron level. Moreover, the binding relationship between HDG and ALOX5 was verified, and HDG could concentration dependently downregulate ALOX5. Furthermore, ALOX5 overexpression eliminated the inhibition of HDG on H/R-induced apoptosis, oxidative stress, and ferroptosis in H9c2 cardiomyocytes. HDG ameliorated myocardial dysfunction and cardiomyocyte injury by reducing apoptosis, oxidative stress, and ferroptosis through inhibiting ALOX5, providing a new perspective on the prevention and treatment of MI/R injury. [ABSTRACT FROM AUTHOR]

Velvet antler polypeptide (VAP) is the active compounds of velvet antler, an animal derived traditional Chinese medicine. In this work, the myocardial ischemia-reperfusion injury (MIRI) model was established to investigate the protective mechanism of VAP on MIRI in rats. Total 90 male Sprague Dawley (SD) rats were divided into the control, model (MIRI), positive (Diltiazem, DLZ, 20 mg/kg), VAP high, medium, low dose (VAP 300, 200, and 100 mg/kg) groups. After 21 days of intragastric administration, the electrocardiogram (ECG) changes in each group were detected. The activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) isoenzymes in serum, and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and catalase (CAT) in myocardial tissue were detected by ELISA. Hematoxylin and eosin (HandE) staining was used to detect the histological changes of rat myocardium. Western blotting (WB) was used to detect the protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADH quinone oxidoreductase 1 (NQO1) in rat myocardial tissue. In the results, ECG showed that the MIRI model was successfully established; VAP can significantly reduce the activities of LDH, CK-MB in serum of rats, increase the activities of SOD, GSH-Px, CAT in myocardial tissue, reduce the activity of MDA in myocardial tissue, reduce interstitial edema and inflammatory infiltration, and improve the structural damage of rat myocardial tissue. The expression levels of HO-1, NQO1 and Nrf2 protein in rat myocardial tissue were up-regulated. In conclusion, VAP can improve the structural damage of rat myocardial tissue, improve the antioxidant activity of myocardial, and reduce oxidative stress injury. The relevant mechanism may be related to the regulation of Nrf2/ARE signaling pathway in rat myocardial tissue by VAP. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of heparinase （HPSE） on myocardial apoptosis, inflammatory response and oxidative damage in myocardial ischemia reperfusion （MI/R） rats. Methods Sixty SD rats were randomly assigned （1∶1∶1∶1） tocontrol group, I/R group, I/R+shRNA-NC group and I/R+Heparanase-shRNA group. The control group was only threaded without ligation after thoracotomy, and the MI/R model was prepared by ligation of the left anterior descending branch of coronary artery. The western blot assay （WB） was used to detect heart function and markers of heart damage in each group. HE staining and TUNEL staining were used to observe the myocardial pathology. The expression of apoptosis-related proteins （Caspase-3, Bax, Bcl-2） and UPRmt marker proteins （LonP1, HSP70） were detected by WB. The contents of superoxide dismutase （SOD） and malondialdehyde （MDA） were detected by kit. The levels of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in peripheral blood were detected by enzyme-linked immunosorbent assay （ELISA）. Results HE staining results showed that the myocardium, epimyma and myocardial fibers were intact and normal in control group. However, the myocardial fibers were bent, myoglobin was dissolved, myocardial muscle nucleus was pyknotic and dissolved, and muscle bundle membrane was ruptured in I/R group and I/R+shRNA-NC group. The epimyocardium was intact in I/R+Heparanase-shRNA group. Moreover, the myocardial fiber bending was significantly improved in I/R+ Heparanase-shRNA group. Additionally, compared with the control group, the expression levels of CK-MB, cTnI, Mb, Caspase-3 protein, Bax protein, MDA, IL-6, TNF-α and HSP70 in I/R group were significantly increased. And the difference was statistically significant. Furthermore, the expression levels of HR, LVEF, LVWT, Bcl-2 protein, SOD and LonP1 protein were significantly decreased. Additionally, compared with the I/R+shRNA-NC group, the expression levels of CK-MB, cTnI, Mb, Caspase-3 protein, Bax protein, MDA, IL-6 and TNF-α in I/R+ Heparanase-shRNA group were significantly decreased. And the difference was statistically significant. However, the expression levels of HR, LVEF, LVWT, Bcl-2 protein, SOD, LonP1 and HSP70 were significantly increased. And the difference was statistically significant. Conclusion Down-regulation of HPSE alleviates myocardial injury in ischemia-reperfusion rats by inhibiting oxidative stress, inflammation, and apoptosis. The mechanism may be related to the inhibition of UPRmt signaling pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effect of dexmedetomidine (Dex ) pretreatment on myocardial ischemia-reperfusion injury (MIRI ) rats and to explore whether its mechanism was related to oxidative stress and Epac1/ Rap1 signaling pathway. Methods SD rats were randomly divided into the sham operation group, model group, Dex group and inhibitor group, with 8 rats in each. Rats in the Dex group were intraperitoneally injected with dexmedetomidine 30 min before modeling. In the inhibitor group, Epac1 antagonists ESI09 and Dex were intraperitoneally injected 30 min and 25 min before modeling. Rats in the sham operation group and model group were intraperitoneally injected with the same dose of normal saline 30 min before modeling. Except the sham operation group, MIRI models were established by ligation of the left coronary artery in other groups. In the sham operation group, the heart was only threaded without ligation of the left coronary artery. Hematoxylin-eosin (HE ) staining was used to observe the pathological changes of myocardial tis⁃ sues. ELISA was used to detect creatine kinase-MB (CK-MB ), lactate dehydrogenase (LDH ), malondialdehyde (MDA ) and superoxide dismutase (SOD ). The expression levels of Epac1 and Rap1 signaling pathway-related proteins in the rat myocardial tissues were detected by Western blotting. Results In the sham operation group, the myocardial fibers were arranged neatly, the edges were clear, and there was no myocardial fiber rupture and intercellular swelling; in the model group, the myocardial fibers showed rupture, disordered arrangement, fuzzy boundary, obvious neutrophil infiltration, and obvious intercellular swelling; in the Dex group and inhibitor group, myocardial fiber rupture, neutrophil infiltration and interstitial swelling were reduced. Serum CK-MB was as follows： LDH model group >Dex group > inhibitor group > sham operation group, the serum MDA was in the following order: model group >Dex group > inhibitor group > sham operation group, serum SOD was as follows： sham operation group > inhibitor group >Dex group > model group, and the expression levels of Epac1 and Rap1 proteins in the myocardial tissues were as follows： model group >Dex group > inhibitor group > sham operation group (all P<0. 05 ). Conclusion Dex preconditioning has a protective effect on myocardial I/R injury rats, and the mechanism may be related to activating Epac1/Rap1 signaling pathway to reduce oxidative stress in the myocardial tissues. [ABSTRACT FROM AUTHOR]

Background: Necroptosis, a novel form of programmed cell death wherein the necrotic morphology is characterized by swelling of the cells, rupture of the plasma membrane, and dysfunction of the organelle, has been always observed in cardiovascular diseases. Sugarcane leaf polysaccharide (SLP) are primary components present in sugarcane leaves that exert cardiovascular protective effects. However, the positive effect of SLP and underlying mechanisms in myocardial ischemia-reperfusion (MI/R) remain unexplored. Aim: In this study, the protective effects of SLP on MI/R injury were investigated under in vitro and in vivo conditions. Methods: The protective effects of SLP on MI/R injury were assessed using tertiary butyl hydrogen peroxide (TBHP)–stimulated-H9c2 cells in the in vitro assay and using Sprague Dawley rats in the in vivo assay. Results: In vitro, SLP significantly reversed TBHP-induced H9c2 cell death by inhibiting necroptosis and oxidative stress. SLP exerted antioxidant activity through the Nrf2/HO-1 pathway. SLP suppressed necroptosis by decreasing phosphorylation of RIP1, RIP3, and MLKL in TBHP-stimulated H9c2 cells. In vivo, SLP attenuated MI/R injury by decreasing the myocardial infarct area; increasing myeloperoxidase and superoxide dismutase levels; and reducing malondialdehyde, interleukin-6, and tumor necrosis factor-α levels.

Myocardial ischemia-reperfusion injury (MI/RI) is a serious obstacle for patients with coronary heart disease (CHD) to benefit from post-ischemic reflow. The low immunogenicity and low carcinogenicity of mesenchymal stem cells (MSCs)-derived exosomes (exo) offer advantage in treating myocardial injuries. Tanshinone IIA (TSA) is an effective drug for MI/RI treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of TSA-pretreated MSC-derived exosomes (TSA-MSC exo) in ameliorating MI/RI in rats. Expectedly, the MI/RI was significantly relieved by TSA-MSC exo compared with MSC exo. Moreover, the overexpression of CCR2 in rats' heart was used to determine CCR2 had a regulatory effect on monocyte infiltration and angiogenesis after MI/RI. MiRNA microarray analysis of MSC exo and TSA-MSC exo revealed miR-223-5p an effective candidate mediator for TSA-MSC exo to exert its cardioprotective function and CCR2 as the downstream target. In summary, our findings indicated that miR-223-5p packaged in TSA-MSC exo inhibited CCR2 activation to reduce monocyte infiltration and enhanced angiogenesis to alleviate MI/RI. Thus, the development of cell free therapies for exosomes derived from the combination TSA and MSC provides an effective strategy for the clinical therapies of ischemic cardiomyopathy. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective To explore the effect and mechanism of vitamin C (VC) injection regulating oxidative stress response to inhibit myocardial ischemia reperfusion injury in rats. Methods A total of 24 wistar rats were anesthetized to establish a model of acute myocardial ischemia-reperfusion injury model, and divided into the normal control group (threading but not ligated in the upper 1/3 of the left coronary artery),the model group (threading and ligated in the upper 1/3 of the left coronary artery),and the VC treatment group (100 mg/kg VC intravenously during reperfusion). Myocardial infarction area was measured by TTC staining, and the percentage of myocardial infarction area in ventricular area was calculated. Immunohistochemistry was used to detect the expression of myocardial tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in each group of rats. The enzyme-linked immunosorbent assay (ELISA) was used to analyze the content changes of oxidative stress indexes [malondialdehyde (MDA) and superoxide dismutase (SOD)]. Western blotting was used to detect the expression of key indicators of inflammation [nuclear factor-κB (NF-κB) p65 and autophagy-hyperactivated proteins (Beclin-1)] in the tissues of each group of rats. Results The area of myocardial infarction increased in myocardial ischemia-reperfusion rats. The myocardial structure of the normal control group was normal, myocardial cells showed no swelling, inflammatory cells and fibrosis changes were not observed in the interstitium. In the model group, myocardial cells were swollen, cytoplasmic staining, myocardial interstitial bleeding with inflammatory cell infiltration and obvious local fibrosis were observed. The expression of TNF-α and IL-6 increased, MDA content increased significantly, SOD content decreased significantly, NF-κB p65 and Beclin-1 protein expression were significantly up-regulated. In the VC treatment group, the area of myocardial infarction was reduced, and myocardial cell swelling was significantly improved with interstitial edema and a small amount of inflammatory cell infiltration, and myocardial bleeding and fibrosis were significantly improved. The expression of TNF-α and IL-6 decreased, which inhibited oxidative stress and down-regulated the protein expression of NF-κB p65 and Beclin-1 in myocardial tissue. The above indexes in the VC treatment group were statistically significant compared with the normal control group and the model group (P＜0.05). Conclusion VC can significantly inhibit the oxidative stress injury after myocardial ischemia reperfusion which was closely related to down-regulating the expression of key indicators of inflammation (NF-κB p65 and Beclin-1) in rats. [ABSTRACT FROM AUTHOR]

Abstract Background NLRP3 inflammasome activation and pyroptosis play a significant role in myocardial ischemia reperfusion injury (MI/RI). Geniposide was reported to show potential therapeutic use for MI/RI with its anti-inflammatory and anti-oxidative properties. However, research on the specific mechanism of geniposide has not been reported. Methods The MIRI model of animal was created in male C57BL/6J mice and the hypoxia reoxygenation (H/R) model was established for the in vitro experiments. Neonatal rat ventricular myocytes (NRVMs) and H9c2 cells with knockdown of TXNIP or NLRP3 were used. Geniposide was administered to mice before vascular ligation. HE staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, echocardiography, oxidative stress and myocardial enzyme detection were used to evaluate the cardioprotective effect of geniposide. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe potential pathway for geniposide cardioprotective in vitro and in vivo. Moreover, ELISA kits were adopted to detect the levels of inflammatory factors, such as IL-1β and IL-18. The gene and protein expression of NLRP3 and pyroptosis-related factors in heart tissue were performed by RT-PCR, western blotting and immunofluorescence in vivo and in vitro, respectively. Results Our results indicate that geniposide can reduce the area of myocardial infarction, improve heart function, and inhibit the inflammatory response in mice after MI/RI. In addition, RT-PCR and western blotting shown geniposide promoting AMPK phosphorylation to activate myocardium energy metabolism and reducing the levels of genes and proteins expression of NLRP3, ASC, N-GSDMD and cleaved caspase-1, IL-1β, IL-18. Meanwhile, geniposide improved NRVMs energy metabolism, which decreased ROS levels and the protein expression of TXNIP and thus suppressed the expression of NLRP3. AMPK antagonist or agonist and siRNA downregulation of TXNIP or NLRP3 were also verify the effect of geniposide against H/R injury. Further research found that geniposide promoted the translocation of TXNIP and reduce the binding of TXNIP and NLRP3. Conclusions In our study, geniposide can significantly inhibit NLRP3 inflammasome activation via the AMPK signaling pathway and inhibit pyroptosis of cardiomyocytes in myocardial tissues.

ABSTRACT Introduction: The objective of this study is to investigate the protective mechanism of dexmedetomidine (Dex) in myocardial ischemia/reperfusion (MIR)-induced acute lung injury (ALI) of diabetic rats by inhibiting hypoxia-inducible factor-1α (HIF-1α). Methods: Initially, healthy male Sprague Dawley rats were treated with streptozocin to induce diabetes. Then, three weeks after the induction, Dex or lentiviral vector (LV)-HIF-1α was injected into the rats 30 minutes prior to the MIR modeling. After four weeks, lung tissues were harvested for pathological changes observation and the wet/dry weight (W/D) ratio determination. Afterwards, oxidative stress indicators and pro-inflammatory factors were measured. In addition, HIF-1α expression was assessed by immunohistochemistry and western blot analysis. Results: Dex could suppress inflammatory cell infiltration, improve lung tissue structure, reduce pathological score and the W/D ratio, and block oxidative stress and inflammatory response in MIR-induced ALI of diabetic rats. Besides, Dex could also inhibit HIF-1α expression. Moreover, Dex + LV-HIF-1α reversed the protective role of Dex on diabetic MIR-induced ALI. Conclusion: Our study has made it clear that Dex inhibited the upregulation of HIF-1α in diabetic MIR-induced ALI, and thus protect lung functions by quenching the accumulation of oxygen radical and reducing lung inflammatory response.

Cardiovascular disease (CVD), a leading cause of morbidity and mortality, is among the most prevalent health problems worldwide and effective strategies for its prevention and treatment are urgently required. In this regard, increasing research has demonstrated that natural drugs offer antihypertensive, antiatherosclerotic, and cardioprotective activities, and many are applied widely for the treatment of CVD and its manifestations such as myocardial infarction, peripheral vascular diseases, and coronary heart disease. Natural drugs have significant advantages in the treatment of CVD due to their efficacy and safety profiles. Saponins are an important class of active components of plant natural products and play an important role in the treatment of CVD. This review covers the most up-to-date information on saponins concerning their cardioprotective effects and mechanisms of action. [ABSTRACT FROM AUTHOR]

Aims: Myocardial ischemia-reperfusion (I/R) injury induces significant apoptosis and reactive oxygen species (ROS) accumulation in cardiomyocytes. Coiled-coil domain-containing 8 (CCDC8), recently identified as an interacting protein of p53, acts as a cofactor in p53-mediated apoptosis. However, its role in myocardial I/R injury remains unclear., Materials and Methods: We first assessed CCDC8 levels in patients with left ventricular failure (LVF) and in both in vivo and in vitro models of myocardial I/R injury. Next, we used adenovirus 9 (AAV9) to overexpress CCDC8 and small interfering RNA (siRNA) to investigate the role of CCDC8 in myocardial I/R injury. mRNA sequencing and KEGG pathway analysis were performed to identify CCDC8-regulated genes. In vitro experiments were conducted to examine the effects of CCDC8 silencing on TNF-α-induced apoptosis., Key Findings: CCDC8 expression was elevated in the left ventricle of LVF patients and in the cardiomyocytes of mice subjected to myocardial I/R injury. Overexpression of CCDC8 in cardiomyocytes via AAV9 exacerbated cardiac dysfunction caused by myocardial I/R injury, while silencing CCDC8 suppressed apoptosis and ROS production in H9c2 cells under hypoxia-reoxygenation (H/R) conditions. mRNA sequencing and KEGG analysis indicated that CCDC8 regulates genes related to cardiac contractility and the TNF signaling pathway. Additionally, CCDC8 silencing reversed TNF-α-induced cardiomyocyte apoptosis in vitro., Significance: This study identifies CCDC8 as a key mediator of cardiomyocyte apoptosis via the TNF signaling pathway in myocardial I/R injury. These findings suggest that targeting CCDC8 could be a potential therapeutic strategy for mitigating cardiac dysfunction in myocardial I/R injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and purpose: Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury. Experimental approach: Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro. Results: Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2. Conclusion: XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.

Pain is one of the most serious problems plaguing human health today. Pain is not an independent pathophysiological condition and is associated with a high impact on elevated disability and organ dysfunction. Several lines of evidence suggested the associations of pain with cardiovascular diseases, especially myocardial ischemia-reperfusion (I/R) injury, while the role of pain in I/R injury and related mechanisms are not yet comprehensively assessed. In this review, we attempted to explore the role of pain in myocardial I/R injury, and we concluded that acute pain protects myocardial ischemia-reperfusion injury and chronic pain aggravates cardiac ischemia-reperfusion injury. In addition, the construction of different pain models and animal models commonly used to study the role of pain in myocardial I/R injury were discussed in detail, and the potential mechanism of pain-related myocardial I/R injury was summarized. Finally, the future research direction was prospected. That is, the remote regulation of pain to cardiac function requires peripheral pain signals to be transmitted from the peripheral to the cardiac autonomic nervous system, which then affects autonomic innervation during cardiac ischemia-reperfusion injury and finally affects the cardiac function.

Objective To explore the action targets and related pathways of eugenol in the treatment of myocardial ischemia-reperfusion injury (MIRI) based on network pharmacology. Methods “Eugenol” was input into TCMSP database to retrieve the action target, and “Myocardial Ischemia Reperfusion Injury” was input into Genecards and OMIM database to retrieve the relevant target of MIRI. After the intersection of the two, the Eugenol-MIRI common target was obtained, which was imported into the string database to establish the protein-protein interaction network (PPI) map, and then was imported into the Cytoscape 3. 7. 2 software for cluster analysis and search for the core target. Eugenol-MIRI common target was introduced into the Matescape gene enrichment analysis online tool data platform for GO function and KEGG pathway enrichment analysis. Results A total of 100 unrepeated eugenol action targets, 1 085 MIRI-related targets and 33 Eugenol-MIRI common targets were obtained. The PPI diagram of Eugenol-MIRI intersection target showed that the average nodal degree of each active ingredient was 7. 09, and the PPI enrichment p-value was 1×10-16. The screening results of core targets based on cluster analysis showed that a total of 2 gene clusters and 2 core genes were obtained, and the core genes were protein kinase B-α (AKT1) and vascular endothelial growth factor A (VEGFA). The results of GO biological function enrichment analysis of Eugenol MIRI common target showed that its main biological processes included positive regulation of protein phosphorylation, ion balance, cell migration, etc., the main cellular components included postsynaptic membrane, membrane raft, membrane microdomains, etc., and the main molecular functions included protein kinase activity, heme binding, transcription factors, etc. There were 177 KEGG enrichment pathways of Eugenol-MIRI common target, mainly including advanced glycation end products (AGE) -receptor for advanced glycation end products (RAGE) signaling pathway, mitogen activated protein kinase (MAPK) signaling pathway, and toll-like receptor (TLR) signaling pathway, etc. Conclusion The core targets of eugenol in the treatment of MIRI mainly include Akt1 and VEGFA, mainly involving AGE-RAGE, MAPK, TLR and other related pathways. [ABSTRACT FROM AUTHOR]

Background: NLRP3 inflammasome activation and pyroptosis play a significant role in myocardial ischemia reperfusion injury (MI/RI). Geniposide was reported to show potential therapeutic use for MI/RI with its anti-inflammatory and anti-oxidative properties. However, research on the specific mechanism of geniposide has not been reported. Methods: The MIRI model of animal was created in male C57BL/6J mice and the hypoxia reoxygenation (H/R) model was established for the in vitro experiments. Neonatal rat ventricular myocytes (NRVMs) and H9c2 cells with knockdown of TXNIP or NLRP3 were used. Geniposide was administered to mice before vascular ligation. HE staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, echocardiography, oxidative stress and myocardial enzyme detection were used to evaluate the cardioprotective effect of geniposide. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe potential pathway for geniposide cardioprotective in vitro and in vivo. Moreover, ELISA kits were adopted to detect the levels of inflammatory factors, such as IL-1β and IL-18. The gene and protein expression of NLRP3 and pyroptosis-related factors in heart tissue were performed by RT-PCR, western blotting and immunofluorescence in vivo and in vitro, respectively. Results: Our results indicate that geniposide can reduce the area of myocardial infarction, improve heart function, and inhibit the inflammatory response in mice after MI/RI. In addition, RT-PCR and western blotting shown geniposide promoting AMPK phosphorylation to activate myocardium energy metabolism and reducing the levels of genes and proteins expression of NLRP3, ASC, N-GSDMD and cleaved caspase-1, IL-1β, IL-18. Meanwhile, geniposide improved NRVMs energy metabolism, which decreased ROS levels and the protein expression of TXNIP and thus suppressed the expression of NLRP3. AMPK antagonist or agonist and siRNA downregulation of TXNIP or NLRP3 were also verify the effect of geniposide against H/R injury. Further research found that geniposide promoted the translocation of TXNIP and reduce the binding of TXNIP and NLRP3. Conclusions: In our study, geniposide can significantly inhibit NLRP3 inflammasome activation via the AMPK signaling pathway and inhibit pyroptosis of cardiomyocytes in myocardial tissues. [ABSTRACT FROM AUTHOR]

Abstract Background Tanshinone I (TI) is a primary component of Salvia miltiorrhiza Bunge (Danshen), which confers a favorable role in a variety of pharmacological activities including cardiovascular protection. However, the exact mechanism of the cardiovascular protection activity of TI remains to be illustrated. In this study, the cardiovascular protective effect and its mechanism of TI were investigated. Methods In this study, tert-butyl hydroperoxide (t-BHP)-stimulated H9c2 cells model was employed to investigate the protective effect in vitro. The cell viability was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) kit. The reactive-oxygen-species (ROS) level and mitochondrial membrane potential (MMP) were investigated by the flow cytometry and JC-1 assay, respectively. While in vivo experiment, the cardiovascular protective effect of TI was determined by using myocardial ischemia–reperfusion (MI/R) model including hematoxylin–eosin (H&E) staining assay and determination of superoxide dismutase (SOD) and malondialdehyde (MDA). Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release were detected by Enzyme-linked immunosorbent assay (ELISA). Receptor interacting protein kinase 1 (RIP1), receptor interacting protein kinase 3 (RIP3), receptor interacting protein kinase 3 (MLKL), protein kinase B (Akt), Nuclear factor erythroid 2 related factor 2 (Nrf2), Heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1) were determined by western blotting. Results Our data demonstrated that TI pretreatment attenuated t-BHP and MI/R injury-induced necroptosis by inhibiting the expression of p-RIP1, p-RIP3, and p-MLKL. TI activated the Akt/Nrf2 pathway to promote the expression of antioxidant-related proteins such as phosphorylation of Akt, nuclear factor erythroid 2 related factor 2 (Nrf2), quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1) expression in t-BHP-stimulated H9c2 cells. TI relieved oxidative stress by mitigating ROS generation and reversing MMP loss. In vivo experiment, TI made electrocardiograph (ECG) recovery better and lessened the degree of myocardial tissue damage. The counts of white blood cell (WBC), neutrophil (Neu), lymphocyte (Lym), and the release of TNF-α and IL-6 were reversed by TI treatment. SOD level was increased, while MDA level was decreased by TI treatment. Conclusion Collectively, our findings indicated that TI exerted cardiovascular protective activities in vitro and in vivo through suppressing RIP1/RIP3/MLKL and activating Akt/Nrf2 signaling pathways, which could be developed into a cardiovascular protective agent.

Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time "window" between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion–induced myocardial damage in donor hearts. Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia–downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Aims Myocardial ischemia is the most common form of cardiovascular disease and the leading cause of morbidity and mortality. Understanding the mechanisms is very crucial for the development of effective therapy. Therefore, this study aimed to investigate the functional roles and mechanisms by which ELAVL1 regulates myocardial ischemia and reperfusion (I/R) injury. Methods Mouse myocardial I/R model and cultured myocardial cells exposed to hypoxia/reperfusion (H/R) were used in this study. Features of ferroptosis were evidenced by LDH activity, GPx4 activity, cellular iron, ROS, LPO, and GSH levels. The expression levels of autophagy markers (Beclin-1, p62, LC3), ELAVL1 and FOXC1 were measured by qRT-PCR, immunostaining and western blot. RIP assay, biotin-pull down, ChIP and dual luciferase activity assay were employed to examine the interactions of ELAVL1/Beclin-1 mRNA and FOXC1/ELAVL1 promoter. CCK-8 assay was used to examine viability of cells. TTC staining was performed to assess the myocardial I/R injury. Results Myocardial I/R surgery induced ferroptosis and up-regulated ELAVL1 level. Knockdown of ELAVL1 decreased ferroptosis and ameliorated I/R injury. Si-ELAVL1 repressed autophagy and inhibition of autophagy by inhibitor suppressed ferroptosis and I/R injury in myocardial cells. Increase of autophagy could reverse the effects of ELAVL1 knockdown on ferroptosis and I/R injury. ELAVL1 directly bound with and stabilized Beclin-1 mRNA. Furthermore, FOXC1 bound to ELAVL1 promoter region and activated its transcription upon H/R exposure. Conclusion FOXC1 transcriptionally activated ELAVL1 may promote ferroptosis during myocardial I/R by modulating autophagy, leading to myocardial injury. Inhibition of ELAVL1-mediated autophagic ferroptosis would be a new viewpoint in the treatment of myocardial I/R injury.

Myocardial ischemia is common in aging population. This study investigates the protective effect of Sevoflurane on myocardial ischemia reperfusion injury (MIRI) and its underlying mechanism. A total of 87 patients with a history of myocardial ischemia who underwent abdominal surgery with Sevoflurane general anesthesia were recruited in the study. The clinical data, blood pressure, heart rate, pressure-rate quotient (PRQ) and rate-pressure product (RPP) were recorded. Serum samples were collected and heart-type fatty acid binding protein (H-FABP), ischemia modified albumin (IMA), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured to observe whether Sevoflurane anesthesia had protective effect on myocardium. In addition, MIRI rats and hypoxia/reoxygenation (H/R) injury cell model was established using neonatal rat ventricular myocytes (NRVM). Rats or NRVM were pretreated with sevoflurane for 45min before hypoxia. The mRNA expression of purinergic receptor-7 (P2X7) and NLR family pyrin domain containing 3(NLRP3) were examined. The protein expression of P2X7, NLRP3, apoptosis-associated speck-like protein (ASC), cysteine aspartic acid specific protease-1(Caspase-1), Gasdermin-D (GSDMD), Bcl-2 Associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2) in myocardial tissue and cells were evaluated. The serum contents of IL-1β, IL-18, Malondialdehyde (MDA), Superoxide dismutase (SOD), Lactate dehydrogenase (LDH), Creatine kinase (CK), and Creatine kinase isoenzymes (CK-MB) were measured. The cellular localization and fluorescence intensity of NLRP3 and ASC in cells were detected. It was found that the secretion of IL-1β and IL-18 decreased in the patients. After I45 min/R3h in SD rats and H3h/R1h in NRVM, the protein expressions of P2X7, NLRP3, ASC, Caspase-1 and GSDMD were increased, the release of IL-1β, IL-18, CK, CK-MB, LDH and MDA were increased, and SOD activity was decreased. Sevoflurane treatment inhibited the high expression of P2X7, NLRP3, ASC, Caspase-1 and GSDMD, inhibited the release of LDH, CK,CK-MB and MDA in cells, and improved the activity of SOD, indicating that Sevoflurane alleviated the damage of MIRI of rats and H/R of NRVM, and had myocardial protective effect. Taken together, our study suggests that Sevoflurane inhibited the expression of IL-1β, IL-18 and GSDMD by inhibiting the P2X7-NLRP3 signaling pathway. It reduced the H/R injury of cardiomyocytes and protected the cardiac function by regulating inflammatory reaction and pyroptosis.

Objective: Myocardial ischemia reperfusion (I/R) damage is a life-threatening vascular emergency after myocardial infarction. Here, we observed the cardioprotective effect of long non-coding RNA (lncRNA) PVT1 knockdown against myocardial I/R damage.Methods: This study constructed a myocardial I/R-induced mouse model and a hypoxia/reoxygenation (H/R)-treated H9C2 cells. PVT1 expression was examined via RT-qPCR. After silencing PVT1 via shRNA against PVT1, H&E, and Masson staining was performed to observe myocardial I/R damage. Indicators of myocardial injury including cTnI, LDH, BNP, and CK-MB were examined by ELISA. Inflammatory factors (TNF-α, IL-1β, and IL-6), Gasdermin D (GSDMD), and Caspase1 were detected via RT-qPCR, western blot, immunohistochemistry, or immunofluorescence. Furthermore, CCK-8 and flow cytometry were presented for detecting cell viability and apoptosis.Results: LncRNA PVT1 was markedly up-regulated in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Silencing PVT1 significantly lowered serum levels of cTnI, LDH, BNP, and CK-MB in myocardial I/R mice. H&E and Masson staining showed that silencing PVT1 alleviated myocardial I/R injury. PVT1 knockdown significantly lowered the production and release of inflammatory factors as well as inhibited the expression of GSDMD-N and Caspase1 in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Moreover, silencing PVT1 facilitated cell viability and induced apoptosis of H/R-treated H9C2 cells.Conclusion: Our findings demonstrated that silencing PVT1 could alleviate myocardial I/R damage through suppressing GSDMD-mediated pyroptosis in vivo and in vitro. Thus, PVT1 knockdown may offer an alternative therapeutic strategy against myocardial I/R damage.

Electroacupuncture (EA) can help reduce infarct size and injury resulting from myocardial ischemia/reperfusion (I/R); however, the underlying molecular mechanism remains unknown. We previously reported that STAT5 plays a critical role in the cardioprotective effect of remote ischemic preconditioning (RIPC). Here, we assessed the effects of electroacupuncture pretreatment (EAP) on myocardial I/R injury in the presence and/or absence of Stat5 in mice and investigated whether EAP exerts its cardioprotective effects in a STAT5-dependent manner. Adult Stat5fl/fl and Stat5-cKO mice were exposed to EAP at Neiguan (PC6) for 7 days before the induction of I/R injury by left anterior descending (LAD) coronary artery ligation. The myocardial infarct size (IS), area at risk, and apoptotic rate of cardiomyocytes were detected. RT-qPCR and western blotting were used to measure gene and protein expression, respectively, in homogenized heart tissues. RNA-seq was used to identify candidate genes and pathways. Our results showed that EAP decreased IS and the rate of cardiomyocyte apoptosis. We further found that STAT5 was activated by EAP in Stat5fl/fl mice but not in Stat5-cKO mice, whereas the opposite was observed for STAT3. Following EAP, the levels of the antiapoptotic proteins Bcl-xL, Bcl-2, and p-AKT were increased in the presence of Stat5, while that of interleukin 10 (IL-10) was increased in both Stat5fl/fl and Stat5-cKO. The gene expression profile in heart tissues was different between Stat5fl/fl and the Stat5-cKO mice with EAP. Importantly, the top 30 DEGs under EAP in the Stat5-cKO mice were enriched in the IL-6/STAT3 signaling pathway. Our results revealed for the first time that the protective effect of EAP following myocardial I/R injury was attributable to, but not dependent on, STAT5. Additionally, we found that EAP could activate STAT3 signaling in the absence of the Stat5 gene, and could also activate antiapoptotic, survival, and anti-inflammatory signaling pathways.

Background: Tanshinone I (TI) is a primary component of Salvia miltiorrhiza Bunge (Danshen), which confers a favorable role in a variety of pharmacological activities including cardiovascular protection. However, the exact mechanism of the cardiovascular protection activity of TI remains to be illustrated. In this study, the cardiovascular protective effect and its mechanism of TI were investigated. Methods: In this study, tert-butyl hydroperoxide (t-BHP)-stimulated H9c2 cells model was employed to investigate the protective effect in vitro. The cell viability was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) kit. The reactive-oxygen-species (ROS) level and mitochondrial membrane potential (MMP) were investigated by the flow cytometry and JC-1 assay, respectively. While in vivo experiment, the cardiovascular protective effect of TI was determined by using myocardial ischemia–reperfusion (MI/R) model including hematoxylin–eosin (H&E) staining assay and determination of superoxide dismutase (SOD) and malondialdehyde (MDA). Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release were detected by Enzyme-linked immunosorbent assay (ELISA). Receptor interacting protein kinase 1 (RIP1), receptor interacting protein kinase 3 (RIP3), receptor interacting protein kinase 3 (MLKL), protein kinase B (Akt), Nuclear factor erythroid 2 related factor 2 (Nrf2), Heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1) were determined by western blotting. Results: Our data demonstrated that TI pretreatment attenuated t-BHP and MI/R injury-induced necroptosis by inhibiting the expression of p-RIP1, p-RIP3, and p-MLKL. TI activated the Akt/Nrf2 pathway to promote the expression of antioxidant-related proteins such as phosphorylation of Akt, nuclear factor erythroid 2 related factor 2 (Nrf2), quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1) expression in t-BHP-stimulated H9c2 cells. TI relieved oxidative stress by mitigating ROS generation and reversing MMP loss. In vivo experiment, TI made electrocardiograph (ECG) recovery better and lessened the degree of myocardial tissue damage. The counts of white blood cell (WBC), neutrophil (Neu), lymphocyte (Lym), and the release of TNF-α and IL-6 were reversed by TI treatment. SOD level was increased, while MDA level was decreased by TI treatment. Conclusion: Collectively, our findings indicated that TI exerted cardiovascular protective activities in vitro and in vivo through suppressing RIP1/RIP3/MLKL and activating Akt/Nrf2 signaling pathways, which could be developed into a cardiovascular protective agent. [ABSTRACT FROM AUTHOR]

Intestinal mucosal barrier dysfunction induced by myocardial ischemia reperfusion (IR) injury often leads to adverse cardiovascular outcomes after myocardial infarction. Early detection and prevention of remote intestinal injury following myocardial IR may help to estimate and improve prognosis after acute myocardial infarction (AMI). This study investigated the protective effect of myocardial ischemic postconditioning (IPo) on intestinal barrier injury induced by myocardial IR and the underlying cellular signaling mechanisms with a focus on the DJ-1. Adult SD rats were subjected to unilateral myocardial IR with or without ischemic postconditioning. After 30 min of ischemia and 120 min of reperfusion, heart tissue, intestine, and blood were collected for subsequent examination. The outcome measures were (i) intestinal histopathology, (ii) intestinal barrier function and inflammatory responses, (iii) apoptosis and oxidative stress, and (iv) cellular signaling changes. IPo significantly attenuated intestinal injury induced by myocardial IR. Furthermore, IPo significantly increased DJ-1, nuclear Nrf2, NQO1, and HO-1 expression in the intestine and inhibited IR-induced apoptosis and oxidative stress. The protective effect of IPo was abolished by the knockdown of DJ-1. Conversely, the overexpression of DJ-1 provided a protective effect similar to that of IPo. Our data indicate that IPo protects the intestine against myocardial IR, which is likely mediated by the upregulation of DJ-1/Nrf2 pathway.

Objective: To study the effects of rosuvastatin preconditioning on autophagy factors and apoptosis-related genes in myocardial ischemia reperfusion injury(MIRI) rats and to analyze their mechanisms. Methods: 60 SD rats were included in the study, and they were randomly divided into sham operation group, model group and pretreatment group, with 20 rats in each group. MIRI models were prepared in both the model group and the pretreatment group. In the sham operation group, thoracotomy was performed in the same way, but only threading was performed without coronary artery ligation. 7 d before the model preparation, the pretreatment group was treated with rosuvastatin 20 mg/(kg·d) by gavage, while the sham operation group and the model group were treated with normal saline5 ml/d. Three groups of rats myocardial tissue apoptosis rate and the myocardial infarction area, left ventricular hemodynamic parameters,the expression of P62, Beclin-1 autophagy related protein, apoptosis-related factor the Bcl-2, Bax and Cyt C protein were compared.Results: The rate of myocardial tissue apoptosis and the area of myocardial infarction in the pretreatment group and the model group were higher than those in the sham operation group, and the pretreatment group was lower than that in the model group(all P<0.05). The left ventricular end diastolic pressure(LVEDP) of rats in the pretreatment group and the model group was higher than that in the sham operation group, and the preconditioning group was lower than that in the model group(all P<0.05). The levels of maximum rate of pressure rise(+dp/dtmax) and the maximum rate of pressure decline(-dp/dtmax) in the left ventricle in the pretreatment group and model group were lower than those in the sham operation group, and the pretreatment group was higher than that in the model group(all P<0.05). Pretreatment group and model group rats P62, Beclin 1 protein expression levels were higher than those in sham operation group, and pretreatment group was lower than the model group(all P<0.05). The m RNA expression levels of Bcl-2 in the pretreatment group and the model group were lower than those in the sham operation group, and the pretreatment group was higher than that in the model group(all P<0.05). The m RNA expression levels of Bax and Cyt C protein expression levels in the pretreatment group and model group were higher than that in the sham operation group, and the pretreatment group was lower than that in the model group(all P<0.05).Conclusion: Rosuvastatin pretreatment can significantly reduce the degree of myocardial tissue damage in MIRI rats, and the main mechanism of action may be related to the effective inhibition of the expression of autophagy factors in myocardial cells and the regulation of apoptosis-related gene expression by rosuvastatin. [ABSTRACT FROM AUTHOR]

Aims: Myocardial ischemia is the most common form of cardiovascular disease and the leading cause of morbidity and mortality. Understanding the mechanisms is very crucial for the development of effective therapy. Therefore, this study aimed to investigate the functional roles and mechanisms by which ELAVL1 regulates myocardial ischemia and reperfusion (I/R) injury. Methods: Mouse myocardial I/R model and cultured myocardial cells exposed to hypoxia/reperfusion (H/R) were used in this study. Features of ferroptosis were evidenced by LDH activity, GPx4 activity, cellular iron, ROS, LPO, and GSH levels. The expression levels of autophagy markers (Beclin-1, p62, LC3), ELAVL1 and FOXC1 were measured by qRT-PCR, immunostaining and western blot. RIP assay, biotin-pull down, ChIP and dual luciferase activity assay were employed to examine the interactions of ELAVL1/Beclin-1 mRNA and FOXC1/ELAVL1 promoter. CCK-8 assay was used to examine viability of cells. TTC staining was performed to assess the myocardial I/R injury. Results: Myocardial I/R surgery induced ferroptosis and up-regulated ELAVL1 level. Knockdown of ELAVL1 decreased ferroptosis and ameliorated I/R injury. Si-ELAVL1 repressed autophagy and inhibition of autophagy by inhibitor suppressed ferroptosis and I/R injury in myocardial cells. Increase of autophagy could reverse the effects of ELAVL1 knockdown on ferroptosis and I/R injury. ELAVL1 directly bound with and stabilized Beclin-1 mRNA. Furthermore, FOXC1 bound to ELAVL1 promoter region and activated its transcription upon H/R exposure. Conclusion: FOXC1 transcriptionally activated ELAVL1 may promote ferroptosis during myocardial I/R by modulating autophagy, leading to myocardial injury. Inhibition of ELAVL1-mediated autophagic ferroptosis would be a new viewpoint in the treatment of myocardial I/R injury. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate whether oxidative stress has a role in myocardial ischemia reperfusion induced renal damage. The 30 male C57 mice were divided into control group, myocardial ischemia reperfusion (MIR) group and MnTBAP treatment group. In MIR group, the left coronary artery was occluded for 45 minutes and reperfusion for 4 weeks. The same procedure was used for the MnTBAP group, with the additional step of MnTBAP (10mg/kg) administered intraperitoneally for 28 days. Before surgery and 4 weeks later, transthoracic echocardiography was performed and urine protein and albumin were measured. At the end of the time, mice were sacrified and kidneys collected for ROS and fibrosis analysis. The plasma was collected for BUN and SCR determination. It was observed that MIR decreased renal function and increased production of ROS, compelled with renal fibrosis. Administration of MnTBAP reduced production of ROS and renal fibrosis and increased renal function. These findings suggest that the MIR plays a causal role in causing renal injury and the MnTBAP exerts renal-protective effects, probably by its antioxidant activities. [ABSTRACT FROM AUTHOR]

Our previous studies showed that Astragaloside IV derivative (LS-102) exhibited potent protective function against ischemia reperfusion (I/R) injury, but little is known about the mechanisms. Mitochondrial fission regulated by dynamin-related protein1 (Drp1) is a newly recognized determinant of mitochondrial function. This study aimed to investigate the protection of LS-102 on mitochondrial structure and function by regulating the activity of Drp1 using models of H9c2 cardiomyocyte injury induced by hypoxia-reperfusion (H/R), and rat heart injury induced by I/R. The results showed that LS-102 significantly decreased apoptosis, levels of ROS, CK, LDH, and calcium, upregulating MMP, and the Bax/Bcl-2 ratio in cardiomyocytes during I/R injury. Furthermore, LS-102 prevented I/R-induced mitochondrial fission by decreasing Drp1’s mitochondrial localization through decreasing the phosphorylation of Drp1 at Ser616 (Drp1Ser616) and increasing the phosphorylation of Drp1 at Ser637 (Drp1Ser637) in H9c2 cells. Importantly, we also robustly confirmed Drp1Ser616 as a novel GSK-3β phosphorylation site. GSK-3β-mediated phosphorylation at Drp1Ser616 may be associated with mitochondrial fission during I/R of cardiomyocytes. In conclusion, LS-102 exerts cardio protection against I/R-induced injury by inhibiting mitochondrial fission via blocking GSK-3β-mediated phosphorylation at Ser616 of Drp1.

Myocardial ischemia reperfusion (MI/R) injury is a severe pathological process that threatens human health all over the world. The role of microRNAs (miRNAs) in the pathogenesis of MI/R injury has been increasingly recognized in recent years. Here, we conducted a miRNA profiling of the hearts of MI/R injured rat model, and identified 46 miRNAs which were differentially expressed between the MI/R injury and the control groups. With a special focus on one of the most significantly changed miRNA, miR-30c-5p, we demonstrated its protective role against cardiomyocyte injury in tBHP-treated H9c2 cells. Overexpression of miR-30c-5p increased cell viability, decreased LDH release, and reduced cell apoptosis of cardiomyocytes after tBHP stimulation, accompanied with downregulated p53 expression. Noticeably, the level of miR-30c-5p was markedly upregulated in MI/R injury cells treated with panax notoginseng saponins (PNS), a traditional Chinese Medicine with significant clinical effects in the treatment of human MI/R injury. Moreover, miR-30c-5p inhibitor is sufficient to block the protection of PNS, as well as its active ingredient ginsenoside Re, against tBHP induced cardiomyocyte injury. The expression of p53 protein was also reduced in PNS treated cells. In summary, our study identified novel miRNA hits of MI/R injury, revealed a pivotal role of miR-30c-5p in cardiomyocyte damage and apoptosis after MI/R, and illustrated a miR-30c-5p-dependent therapeutic mechanism of PNS of this pathologic process. Future studies are warranted to examine the endogenous significance of miR-30c-5p, along with multiple other miRNA hits, in the pathogenesis and treatment of MI/R injury.

Background/Aims: Myocardial reperfusion has the potential to salvage the ischemic myocardium after a period of coronary occlusion. Reperfusion, however, can cause a wide spectrum of deleterious effects. Galectin-3 (GAL-3), a beta galactoside binding lectin, is closely associated with myocardial infarction (MI), myocardial fibrosis and heart failure. In our study, we investigated its role in ischemia-reperfusion injuries (IR) as this phenomenon is extremely relevant to the early intervention after acute MI. Methods: C57B6/J wild type (WT) mice and GAL-3 knockout (KO) mice were used for murine model of IR injury in the heart where a period of 30 minutes ischemia was followed by 24 hours of reperfusion. Heart samples were processed for immunohistochemical and immunofluorescent labeling, morphometric analysis, western blot and enzyme-linked immunosorbent assay to identify the apoptotic, inflammatory and oxidative stress role of GAL-3. Results: Our results show that there was a significant increase in GAL-3 levels in the heart which shows GAL-3 is playing a role in the ischemia reperfusion injury. Troponin I was also significantly higher in GAL-3-KO group than wild type. Our study shows that GAL-3 is associated with an increase in the antioxidant activity in the IR injured myocardium. Antioxidant enzymes superoxide dismutase, glutathione and catalase were found to be significantly raised in the GAL-3 wild type IR as compared to the GAL-3 KO IR group. A significant increase in apoptotic activity is seen in GAL-3 KO IR group as compared with GAL-3 wild IR group. Conclusion: Our study shows that GAL-3 can affect the redox pathways, controlling cell survival and death, and plays a protective role on the myocardium following IR injury.

The mechanisms underlying beneficial actions of Rutin, a food derived-polyphenolic bioflavonoid, against myocardial ischemia-reperfusion (MI/R) injury were detected. We found that Rutin could significantly ameliorate infarct size and attenuate cardiac dysfunctionto in some extent. Additionally, Rutin could also improve variation of myocardial zymogram and up-regulate antioxidant systems in heart. The selective SIRT1 inhibitor, Ex-527, exacerbated MI/R injury as evidenced by further increased oxidative stress and infracted area in heart tissue. Importantly, Ex-527 abolished the cardioprotective effect of Rutin in MI/R rats. Docking analysis further demonstrated the vital role of SIRT1 on Rutin's cardioprotective effect. We found that activation of SIRT1/Nrf2 signaling induced by Rutin contributes to the reduced oxidative stress, along with decreased apoptosis of cardiomyocytes in heart tissue. Overall, our findings suggest that SIRT1/Nrf2 signaling pathway may be a potential therapeutic target for the treatment of oxidative stress and apoptosis related myocardial diseases.

Bangming Cao,* Chi Zhang,* Haipeng Wang, Ming Xia, Xiangjun Yang Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China *These authors contributed equally to this work Background: Whether upper arm remote ischemic postconditioning (RIPostC) exerts protection to kidney in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains unknown. Methods: Sixty-four patients with STEMI were randomized to PPCI + RIPostC (n=29) and PPCI (n=35) groups. RIPostC consisting of 4 cycles of 5 minutes occlusion/reperfusion by cuff inflation/deflation of the upper arm was started within 1 minute after the first balloon dilatation. Peripheral venous blood samples were collected before PPCI and at 0.5, 8, 24, 48, and 72 hours after PPCI to detect serum creatinine (SCr) and creatine kinase-MB (CK-MB). Acute kidney injury (AKI) rate and estimated glomerular filtration rate (eGFR) were calculated. The transthoracic echocardiography was performed 7 days after PPCI to assess left ventricular ejection fraction (LVEF). Results: The patients in the PPCI + RIPostC group had a lower AKI rate compared with those in the PPCI group (P=0.04). The eGFR after PPCI increased in the PPCI + RIPostC group compared to the PPCI group (P

Objective: To study the effect of fructose 1,6-diphosphate (FDP) on myocardial ischemia reperfusion injury in rats and its molecular mechanism. Methods: Male SPF SD rats were selected as experimental animals and randomly divided into four groups. Sham group received sham operation, I/R group were made into myocardial ischemia reperfusion injury models, FDP group were made into myocardial ischemia reperfusion injury models and then were given FDP intervention, and FDP+AG490 group were made into myocardial ischemia reperfusion injury models and then were given FDP and JAK2 inhibitor AG490 intervention. Results: CK, CK-MB, cTnI and LDH contents in serum as well as Bax and Caspase-3 protein expression in myocardial tissue of I/R group were significantly higher than those of Sham group whereas Bcl-2, p-JAK2 and p-STAT3 protein expression in myocardial tissues were significantly lower than those of Sham group; CK, CK-MB, cTnI and LDH contents in serum as well as Bax and Caspase-3 protein expression in myocardial tissue of FDP group were significantly lower than those of I/R group whereas Bcl-2, p-JAK2 and p-STAT3 protein expression in myocardial tissue were significantly higher than those of I/R group; CK, CK-MB, cTnI and LDH contents in serum as well as Bax and Caspase-3 protein expression in myocardial tissue of FDP+AG490 group were significantly higher than those of FDP group whereas Bcl-2 protein expression in myocardial tissue was significantly lower than that of FDP group. Conclusion: FDP could reduce the myocardial ischemia reperfusion injury in rats by activating the JAK2/STAT3 pathway.

Our previous studies showed that Astragaloside IV derivative (LS-102) exhibited potent protective function against ischemia reperfusion (I/R) injury, but little is known about the mechanisms. Mitochondrial fission regulated by dynamin-related protein1 (Drp1) is a newly recognized determinant of mitochondrial function. This study aimed to investigate the protection of LS-102 on mitochondrial structure and function by regulating the activity of Drp1 using models of H9c2 cardiomyocyte injury induced by hypoxia-reperfusion (H/R), and rat heart injury induced by I/R. The results showed that LS-102 significantly decreased apoptosis, levels of ROS, CK, LDH, and calcium, upregulating MMP, and the Bax/Bcl-2 ratio in cardiomyocytes during I/R injury. Furthermore, LS-102 prevented I/R-induced mitochondrial fission by decreasing Drp1's mitochondrial localization through decreasing the phosphorylation of Drp1 at Ser616 (Drp1Ser616) and increasing the phosphorylation of Drp1 at Ser637 (Drp1Ser637) in H9c2 cells. Importantly, we also robustly confirmed Drp1Ser616 as a novel GSK-3β phosphorylation site. GSK-3β-mediated phosphorylation at Drp1Ser616 may be associated with mitochondrial fission during I/R of cardiomyocytes. In conclusion, LS-102 exerts cardio protection against I/R-induced injury by inhibiting mitochondrial fission via blocking GSK-3β-mediated phosphorylation at Ser616 of Drp1. [ABSTRACT FROM AUTHOR]

In this study, the regulation of miR-15b-5p on myocardial ischemia reperfusion (I/R) injury-induced arrhythmia and myocardial apoptosis was investigated in mice. We observed the change in miR-15b-5p expression after mice suffered from myocardial I/R injury and the change in myocardial injury, infarct size, apoptosis, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD) and malondialdehyde (MDA) after down-regulation of miR-15b-5p expression. The negative regulation of miR-15b-5p to KCNJ2 as well as whether cardioprotective effect formed by miR-15b-5p down-regulation relied on the increase of KNCJ2 expression were measured by dual-luciferase reporter assay system. miR-15b-5p expression increased and KCNJ2 mRNA and protein expressions decreased after myocardial ischemia reperfusion (all P < 0.05). miR-15b-5p negatively regulated KCNJ2 in a targeted way. Down-regulating miR-15b-5p expression or increasing KCNJ2 expression significantly decreased the incidence of arrhythmia, infarct size and apoptosis after myocardial I/R and lowered MDA content in the myocardial tissue as well as IL-6 and TNF-α content in the blood (all P < 0.05). KCNJ2 gene knockout reversed the above cardioprotective effect formed by miR-15b-5p down-regulation (P < 0.05). Down-regulating miR-15b-5p expression or up-regulating KCNJ2 expression improves arrhythmia after mice suffered from myocardial I/R injury and inhibits myocardial apoptosis. • Myocardial ischemia reperfusion can effectively remedy myocardial infarction. • miR-15b-5p can regulate cardiac disease, apoptosis and inflammatory injury. • miR-15b-5p can restrain I/R injury-induced arrhythmia and myocardial apoptosis. [ABSTRACT FROM AUTHOR]

To investigate the effects of propofol on myocardial ischemia reperfusion in rats with type 2 diabetes, male adult rats were divided into five groups: Sham-operation (CC), ischemia-reperfusion (CI), low-dose propofol (LP), moderate-dose propofol (MP) and high-dose propofol (HP). The LP, MP and HP groups were administered with 6, 12 and 24 mg/kg/h propofol, respectively, prior to occlusion. Heart rate (HR), left ventricular systolic pressure (LVSP) and the rate (dp/dt max) of left ventricular pressure rise in early systole (±dp/dt max) were recorded. The role of autophagy was also studied by measuring the levels of superoxide dismutase (SOD), malondialdehyde (MDA), autophagy marker protein LC3II, mammalian target of rapamycin (mTOR)/phosphorylate (p)-mTOR and cardiac troponin T (cTnT). The myocardial morphological features were assessed using light and electron microscopy. The present results demonstrated that the HR, LVSP, +dp/dt and -dp/dt levels in the propofol groups (LP, MP and HP) were significantly increased (P<0.05) when compared with the CI group. The myocardial cells in the MP group showed mild edematous changes and partially dissolved mitochondrial cristae and membrane rupture. SOD, cTnT and MDA levels were significantly decreased (P<0.05), mTOR expression decreased significantly (P<0.05) and p-mTOR expression increased significantly in the MP group (P<0.05). The present study demonstrated the protective effects of propofol in T2DM rats exhibiting MIRI, with an optimal protective effect at an infusion rate of 12 mg/kg/h. Additionally, the results revealed that propofol led to significant reductions in LC3II and mTOR serum levels and the inhibition of autophagy in myocardial cells. [ABSTRACT FROM AUTHOR]

Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17β-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection. [ABSTRACT FROM AUTHOR]

Excessive reactive oxygen species (ROS) induced by myocardial ischemia reperfusion (IR) injury exert detrimental effects on cardiomyocytes. Antioxidant peptides can scavenge free radicals such as 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitic oxide (NO) in vitro, but little is known about their functions in vivo. Here, we evaluated the effects of an antioxidant peptide (antioxidant-RL) used at the beginning of reperfusion on myocardial IR injury. We performed 2, 3, 5-triphenyltetrazolium chloride staining (TTC) to determine myocardial infarct size. Creatine kinase isoenzyme-MB (CK-MB), cardiac troponin-T (CTnT), tumor necrosis factoralpha (TNF-a), and interleukin-6 (IL-6) levels were determined with enzyme-linked immunosorbent assays (ELISAs). The levels of ROS were measured with a fluorometric Intracellular ROS kit. The expression levels of apoptosis-related proteins in cardiomyocytes were detected by western blotting. Antioxidant-RL (10 mg/kg) reduced the infarct size and levels of CK-MB and CTnT in rats. The levels of TNF-a and IL-6 also decreased. Furthermore, ROS levels were ameliorated and the expression of apoptosis-related proteins in myocytes was down-regulated by antioxidant-RL (100 µg/mL). Antioxidant-RL exerted protective effects on myocardial IR injury by scavenging excessive ROS, suppressing inflammatory factors, and inhibiting cardiomyocytes apoptosis. Thus, antioxidant-RL may serve as a potent candidate for the treatment of IR injury. [ABSTRACT FROM AUTHOR]

Background: Effective interventions to improve the outcome of patients subjected to myocardial ischemia reperfusion (MI/R) are urgent in clinical settings. Tanshinone IIA (TSA) is reported to attenuate myocardial injury and improve ventricular remodeling post MI/R. Here, we evaluated the efficacy of AFC1 compound that is similar to TSA structure in murine MI/R models. We found that AFC1 had a comparable effect of improving murine cardiac function after MI/R while it was superior to TSA in safety profile. Administration of AFC1 reduced reactive oxygen species (ROS) production, inflammatory cells infiltration, and the expression of platelet derived growth factor receptors (PDGFR) in infarcted myocardium. Treatment with AFC1 also attenuated MI/R-induced cardiac remodeling and contributed to the recovery of cardiac function. Additionally, AFC1 reversed the elevation of PDGFR expression induced by PDGF-AB in both neonatal rat cardiomyocytes (NCMs) and neonatal rat cardiac fibroblasts (NCFs) and suppressed PDGF-AB induced NCM hypertrophy via STAT3 pathway and NCF collagen synthesis through p38-MAPK signaling in vitro. Similarly, AFC1 may contribute to the recovery of cardiac function in mice post MI/R via suppressing STAT signaling. Our results confirmed that AFC1 exerts anti-hypertrophic and anti-fibrotic effects against MI/R-induced cardiac remodeling, and suggest that AFC1 may have a promising potential in improving the outcome of patients who suffered from MI/R.

Aim: (-)-Epicatechin (EPI) has physiological activities such as antioxidant, anti-inflammatory and immune enhancement. In this study, we elucidated the protective effects of EPI in myocardial ischemia/reperfusion injury (MI/RI) and its mechanisms., Methods: An in vivo I/R model was constructed by performing left anterior descending coronary artery surgery on rats, and an in vitro I/R model was constructed by subjecting hypoxia/reperfusion treatment on H9C2 cells. The damage of cardiac tissues was detected by 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (H&E) staining, and expressions of ferroptosis-related proteins were examined by Western blot. Changes in the number of autophagosomes, the levels of oxidative stress and Fe 2+ were also examined., Results: EPI reduced abnormal electrocardiogram waveform and infarct size caused by MI/RI in rats. The increasing trend of levels of reactive oxygen species (ROS) and Fe 2+ was reversed by EPI, suggesting that EPI can reduce ferroptosis in vivo . Moreover, the levels of lipid ROS and LC3 in H9C2 cells were decreased with EPI treatment, and autophagy and ferroptosis were also alleviated in a dose-dependent manner in vitro . Co-cultivation of USP14 inhibitor IU1 and EPI further revealed that EPI regulates ferroptosis through the USP14-autophagy pathway., Conclusions: EPI can reduce the level of oxidative stress by promoting USP14 to reduce autophagy, thus inhibiting autophagy dependent ferroptosis and reducing oxidative stress, and has a protective effect on myocardial infarction/myocardial infarction.

Background: Effective interventions to improve the outcome of patients subjected to myocardial ischemia reperfusion (MI/R) are urgent in clinical settings. Tanshinone IIA (TSA) is reported to attenuate myocardial injury and improve ventricular remodeling post MI/R. Here, we evaluated the efficacy of AFC1 compound that is similar to TSA structure in murine MI/R models. We found that AFC1 had a comparable effect of improving murine cardiac function after MI/R while it was superior to TSA in safety profile. Administration of AFC1 reduced reactive oxygen species (ROS) production, inflammatory cells infiltration, and the expression of platelet derived growth factor receptors (PDGFR) in infarcted myocardium. Treatment with AFC1 also attenuated MI/R-induced cardiac remodeling and contributed to the recovery of cardiac function. Additionally, AFC1 reversed the elevation of PDGFR expression induced by PDGF-AB in both neonatal rat cardiomyocytes (NCMs) and neonatal rat cardiac fibroblasts (NCFs) and suppressed PDGF-AB induced NCM hypertrophy via STAT3 pathway and NCF collagen synthesis through p38-MAPK signaling in vitro. Similarly, AFC1 may contribute to the recovery of cardiac function in mice post MI/R via suppressing STAT signaling. Our results confirmed that AFC1 exerts anti-hypertrophic and anti-fibrotic effects against MI/R-induced cardiac remodeling, and suggest that AFC1 may have a promising potential in improving the outcome of patients who suffered from MI/R. [ABSTRACT FROM AUTHOR]

Objective To optimize the emergency treatment process for acute ST-segment elevation myocardial infarction (STEMI). Methods A multidisciplinary team was established to design the flowchart of the myocardial ischemia reperfusion process for acute STEMI patients. Guided by the 3C theory, the method of ECRSAI (E-Eliminate; C-Combine; R-Rearrange; S-Simplify; A-Automate; I-Integrate) was adopted and related interventions was conducted. A total of 76 acute STEMI patients undergoing percutaneous coronary intervention (PCI) between June and December 2017 were set as the control group, and another 78 patients undergoing PCI between January and June 2018 were set as the intervention. The routine process of emergency treatment was adopted in the control group, and the optimized process was carried out in the intervention group. Results After the implementation of the optimized process, the door-to-balloon time was reduced from 87 (75,105) min to 61.5 (42.75, 70) min. The ratio of patients with the door-to-balloon time ≤ 90min increased from 63.2% to 94.9% (P<0.01). Conclusion Utilization ECRSAI method to optimize the Myocardial ischemia reperfusion process can effectively shorten the door-to-balloon time in emergency treatment of STEMI. [ABSTRACT FROM AUTHOR]

Abstract Chronic pain aggravates cardiovascular injury via incompletely understood mechanisms. While melatonin may participate in the pathophysiological process of chronic pain, its cardiovascular effects under chronic pain states remains unknown. In this study, chronic pain was induced by spared nerve injury model (SNI) for 4 weeks. We showed decreased the ipsilateral hind paw withdrawal mechanical threshold (PWMT) in SNI mice. High dose melatonin treatment (60 mg/kg, i.p.) could reversed nociceptive threshold in SNI mice. To verify the effect of chronic pain on the cardiac tolerance to ischemic stress, mice were subjected to myocardial ischemia-reperfusion (MI/R) in vivo. SNI mice showed exaggerated MI/R-induced detrimental effects and myocardial necroptosis compared with control group (P <.05). Mechanically, an increased level of tumor necrosis factor-α (TNF-α) was found in SNI group following by a robust interaction of RIP1/RIP3. RIP3-induced phosphor-MLKL and CaMKII more significantly in SNI mice (P <.05). We found that RIP3 deficiency provided a comparable protection against MI/R-induced necroptosis under chronic pain conditions. More importantly, low dose melatonin (20 mg/kg, i.p.) treatment 10 min before reperfusion decreased the level of TNF-α following with a negatively regulating the RIP3 induced phosphor-MLKL/CaMKII signaling, thus significantly reduced ROS production and cardiomyocyte necroptosis and ameliorated cardiac function. In summarize, our results demonstrated that chronic pain sensitizes heart to MI/R injury and myocardial necrosis plays an important role in this pathophysiological process. We also define melatonin acted as triple cardioprotective effects: ameliorating TNF-α level, suppressing RIP3-MLKL/CaMKII signaling induced necroptosis and exerting analgesia effect. [ABSTRACT FROM AUTHOR]

Background: Necroptosis, a novel form of programmed cell death wherein the necrotic morphology is characterized by swelling of the cells, rupture of the plasma membrane, and dysfunction of the organelle, has been always observed in cardiovascular diseases. Sugarcane leaf polysaccharide (SLP) are primary components present in sugarcane leaves that exert cardiovascular protective effects. However, the positive effect of SLP and underlying mechanisms in myocardial ischemia-reperfusion (MI/R) remain unexplored., Aim: In this study, the protective effects of SLP on MI/R injury were investigated under in vitro and in vivo conditions., Methods: The protective effects of SLP on MI/R injury were assessed using tertiary butyl hydrogen peroxide (TBHP)-stimulated-H9c2 cells in the in vitro assay and using Sprague Dawley rats in the in vivo assay., Results: In vitro , SLP significantly reversed TBHP-induced H9c2 cell death by inhibiting necroptosis and oxidative stress. SLP exerted antioxidant activity through the Nrf2/HO-1 pathway. SLP suppressed necroptosis by decreasing phosphorylation of RIP1, RIP3, and MLKL in TBHP-stimulated H9c2 cells. In vivo , SLP attenuated MI/R injury by decreasing the myocardial infarct area; increasing myeloperoxidase and superoxide dismutase levels; and reducing malondialdehyde, interleukin-6, and tumor necrosis factor-α levels., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background/Aims: Myocardial reperfusion has the potential to salvage the ischemic myocardium after a period of coronary occlusion. Reperfusion, however, can cause a wide spectrum of deleterious effects. Galectin-3 (GAL-3), a beta galactoside binding lectin, is closely associated with myocardial infarction (MI), myocardial fibrosis and heart failure. In our study, we investigated its role in ischemia-reperfusion injuries (IR) as this phenomenon is extremely relevant to the early intervention after acute MI. Methods: C57B6/J wild type (WT) mice and GAL-3 knockout (KO) mice were used for murine model of IR injury in the heart where a period of 30 minutes ischemia was followed by 24 hours of reperfusion. Heart samples were processed for immunohistochemical and immunofluorescent labeling, morphometric analysis, western blot and enzyme-linked immunosorbent assay to identify the apoptotic, inflammatory and oxidative stress role of GAL-3. Results: Our results show that there was a significant increase in GAL-3 levels in the heart which shows GAL-3 is playing a role in the ischemia reperfusion injury. Troponin I was also significantly higher in GAL-3-KO group than wild type. Our study shows that GAL-3 is associated with an increase in the antioxidant activity in the IR injured myocardium. Antioxidant enzymes superoxide dismutase, glutathione and catalase were found to be significantly raised in the GAL-3 wild type IR as compared to the GAL-3 KO IR group. A significant increase in apoptotic activity is seen in GAL-3 KO IR group as compared with GAL-3 wild IR group. Conclusion: Our study shows that GAL-3 can affect the redox pathways, controlling cell survival and death, and plays a protective role on the myocardium following IR injury. [ABSTRACT FROM AUTHOR]