The detrimental role of galectin-3 and endoplasmic reticulum stress in the cardiac consequences of myocardial ischemia in the context of obesity.

The association between cardiac fibrosis and galectin-3 was evaluated in patients with acute myocardial infarction (MI). The role of galectin-3 and its association with endoplasmic reticulum (ER) stress activation in the progression of cardiovascular fibrosis was also evaluated in obese-infarcted rats. The inhibitor of galectin-3 activity, modified citrus pectin (MCP; 100 mg/kg/day), and the inhibitor of the ER stress activation, 4-phenylbutyric acid (4-PBA; 500 mg/kg/day), were administered for 4 weeks after MI in obese rats. Overweight-obese patients who suffered a first MI showed higher circulating galectin-3 levels, higher extracellular volume, and LV infarcted size, as well as lower E/e'ratio and LVEF compared with normal-weight patients. A correlation was observed between galectin-3 levels and extracellular volume. Obese-infarcted animals presented cardiac hypertrophy and reduction in LVEF, and E/A ratio as compared with control animals. They also showed an increase in galectin-3 gene expression, as well as cardiac fibrosis and reduced autophagic flux. These alterations were associated with ER stress activation characterized by enhanced cardiac levels of binding immunoglobulin protein, which were correlated with those of galectin-3. Both MCP and 4-PBA not only reduced cardiac fibrosis, oxidative stress, galectin-3 levels, and ER stress activation, but also prevented cardiac functional alterations and ameliorated autophagic flux. These results show the relevant role of galectin-3 in the development of diffuse fibrosis associated with MI in the context of obesity in both the animal model and patients. Galectin-3 in tandem with ER stress activation could modulate different downstream mechanisms, including inflammation, oxidative stress, and autophagy.

[MiR-224-5p overexpression inhibits oxidative stress by regulating the PI3K/Akt/FoxO1 axis to attenuate hypoxia/reoxygenation-induced cardiomyocyte injury].

OBJECTIVES: To investigate the regulatory role of miRNA-224-5p in hypoxia/reoxygenation (H/R) -induced H9c2 cardiomyocyte injury. METHODS: Plasma samples were collected from 160 patients with acute myocardial infarction and 80 healthy controls(HC) to measure miRNA-224-5p levels and other biochemical parameters. In cultured H9c2 cells with H/R injury, the effects of transfection with miR-224-5p mimics or a negative control sequence on cell viability, malondialdehyde (MDA) content, and superoxide dismutase 2 (SOD2) and lactate dehydrogenase (LDH) activities were tested. Dual luciferase reporter gene assay was performed to verify the targeting relationship between miR-224-5p and PTEN. Bioinformatics methods were used to analyze the potential mechanisms of the target genes. The expression of miRNA-224-5p in the treated cells was detected with qRT-PCR, the protein expressions of PTEN, Bcl-2, Bax, cleaved caspase-3, SOD2, p-PI3K/PI3K, p-Akt/Ak and p-FoxO1/FoxO1 were determined using Western blotting, and cell apoptosis was analysed with flow cytometry. RESULTS: The levels of blood glucose, C-reactive protein, CK, CK-MB and cTnI were significantly higher in the AMI group compared with the HC group (P < 0.05). The expression level of miR-224-5p was significantly lowered in patients with STEMI and NSTEMI and in H9c2 cells with H/R injury. The viability of H9c2 cells decreased time-dependently following H/R injury. PTEN was a target gene of miR-224-5p, and the PI3K/Akt pathway was the most significantly enriched pathway. H9c2 cells with H/R injury showed significantly decreased SOD2 activity, increased LDH activity and MDA content, increased cell apoptosis, decreased protein expression levels of p-PI3K, p-Akt, p-FoxO1, SOD2, and Bcl-2, and increased expressions of PTEN, Bax, and cleaved caspase-3. These changes were obviously attenuated by trasnfection of the cells with miR-224-5p mimics prior to H/R exposure. CONCLUSION: MiR-224-5p overexpression upregulates the expression of the antioxidant gene SOD2 through the PI3K/Akt/FoxO1 axis to relieve H/R-induced oxidative stress and reduce apoptosis of H9c2 cells.

The orchestration of cell-cycle reentry and ribosome biogenesis network is critical for cardiac repair.

Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.

Roxadustat Attenuates Adverse Remodeling Following Myocardial Infarction in Mice.

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. METHODS: We evaluated roxadustat's impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.

The Influence of Metabolic Risk Factors on the Inflammatory Response Triggered by Myocardial Infarction: Bridging Pathophysiology to Treatment.

Myocardial infarction (MI) sets off a complex inflammatory cascade that is crucial for effective cardiac healing and scar formation. Yet, if this response becomes excessive or uncontrolled, it can lead to cardiovascular complications. This review aims to provide a comprehensive overview of the tightly regulated local inflammatory response triggered in the early post-MI phase involving cardiomyocytes, (myo)fibroblasts, endothelial cells, and infiltrating immune cells. Next, we explore how the bone marrow and extramedullary hematopoiesis (such as in the spleen) contribute to sustaining immune cell supply at a cardiac level. Lastly, we discuss recent findings on how metabolic cardiovascular risk factors, including hypercholesterolemia, hypertriglyceridemia, diabetes, and hypertension, disrupt this immunological response and explore the potential modulatory effects of lifestyle habits and pharmacological interventions. Understanding how different metabolic risk factors influence the inflammatory response triggered by MI and unraveling the underlying molecular and cellular mechanisms may pave the way for developing personalized therapeutic approaches based on the patient's metabolic profile. Similarly, delving deeper into the impact of lifestyle modifications on the inflammatory response post-MI is crucial. These insights may enable the adoption of more effective strategies to manage post-MI inflammation and improve cardiovascular health outcomes in a holistic manner.

Mst1/Hippo signaling pathway drives isoproterenol-induced inflammatory heart remodeling.

Isoproterenol (ISO) administration is a well-established model for inducing myocardial injury, replicating key features of human myocardial infarction (MI). The ensuing inflammatory response plays a pivotal role in the progression of adverse cardiac remodeling, characterized by myocardial dysfunction, fibrosis, and hypertrophy. The Mst1/Hippo signaling pathway, a critical regulator of cellular processes, has emerged as a potential therapeutic target in cardiovascular diseases. This study investigates the role of Mst1 in ISO-induced myocardial injury and explores its underlying mechanisms. Our findings demonstrate that Mst1 ablation in cardiomyocytes attenuates ISO-induced cardiac dysfunction, preserving cardiomyocyte viability and function. Mechanistically, Mst1 deletion inhibits cardiomyocyte apoptosis, oxidative stress, and calcium overload, key contributors to myocardial injury. Furthermore, Mst1 ablation mitigates endoplasmic reticulum (ER) stress and mitochondrial fission, both of which are implicated in ISO-mediated cardiac damage. Additionally, Mst1 plays a crucial role in modulating the inflammatory response following ISO treatment, as its deletion suppresses pro-inflammatory cytokine expression and neutrophil infiltration. To further investigate the molecular mechanisms underlying ISO-induced myocardial injury, we conducted a bioinformatics analysis using the GSE207581 dataset. GO and KEGG pathway enrichment analyses revealed significant enrichment of genes associated with DNA damage response, DNA repair, protein ubiquitination, chromatin organization, autophagy, cell cycle, mTOR signaling, FoxO signaling, ubiquitin-mediated proteolysis, and nucleocytoplasmic transport. These findings underscore the significance of Mst1 in ISO-induced myocardial injury and highlight its potential as a therapeutic target for mitigating adverse cardiac remodeling. Further investigation into the intricate mechanisms of Mst1 signaling may pave the way for novel therapeutic interventions for myocardial infarction and heart failure.

Exploring the role of CBLB in acute myocardial infarction: transcriptomic, microbiomic, and metabolomic analyses.

BACKGROUND: Specific alterations in gut microbiota and metabolites have been linked to AMI, with CBLB potentially playing an essential role. However, the precise interactions remain understudied, creating a significant gap in our understanding. This study aims to address this by exploring these interactions in CBLB-intervened AMI mice using transcriptome sequencing, 16 S rDNA, and non-targeted metabolite analysis. METHODS: To probe the therapeutic potential and mechanistic underpinnings of CBLB overexpression in AMI, we utilized an integrative multi-omics strategy encompassing transcriptomics, metabolomics, and 16s rDNA sequencing. We selected these particular methods as they facilitate a holistic comprehension of the intricate interplay between the host and its microbiota, and the potential effects on the host's metabolic and gene expression profiles. The uniqueness of our investigation stems from utilizing a multi-omics approach to illuminate the role of CBLB in AMI, an approach yet unreported to the best of our knowledge. Our experimental protocol encompassed transfection of CBLB lentivirus-packaged vectors into 293T cells, followed by subsequent intervention in AMI mice. Subsequently, we conducted pathological staining, fecal 16s rDNA sequencing, and serum non-targeted metabolome sequencing. We applied differential expression analysis to discern differentially expressed genes (DEGs), differential metabolites, and differential microbiota. We performed protein-protein interaction analysis to identify core genes, and conducted correlation studies to clarify the relationships amongst these core genes, paramount metabolites, and key microbiota. RESULTS: Following the intervention of CBLB in AMI, we observed a significant decrease in inflammatory cell infiltration and collagen fiber formation in the infarcted region of mice hearts. We identified key changes in microbiota, metabolites, and DEGs that were associated with this intervention. The findings revealed that CBLB has a significant correlation with DEGs, differential metabolites and microbiota, respectively. This suggests it could play a pivotal role in the regulation of AMI. CONCLUSION: This study confirmed the potential of differentially expressed genes, metabolites, and microbiota in AMI regulation post-CBLB intervention. Our findings lay groundwork for future exploration of CBLB's role in AMI, suggesting potential therapeutic applications and novel research directions in AMI treatment strategies.

Aerobic training attenuates cardiac remodeling in mice post-myocardial infarction by inhibiting the p300/CBP-associated factor.

Aerobic training (AT), an effective form of cardiac rehabilitation, has been shown to be beneficial for cardiac repair and remodeling after myocardial infarction (MI). The p300/CBP-associated factor (PCAF) is one of the most important lysine acetyltransferases and is involved in various biological processes. However, the role of PCAF in AT and AT-mediated cardiac remodeling post-MI has not been determined. Here, we found that the PCAF protein level was significantly increased after MI, while AT blocked the increase in PCAF. AT markedly improved cardiac remodeling in mice after MI by reducing endoplasmic reticulum stress (ERS). In vivo, similar to AT, pharmacological inhibition of PCAF by Embelin improved cardiac recovery and attenuated ERS in MI mice. Furthermore, we observed that both IGF-1, a simulated exercise environment, and Embelin protected from H2O2-induced cardiomyocyte injury, while PCAF overexpression by viruses or the sirtuin inhibitor nicotinamide eliminated the protective effect of IGF-1 in H9C2 cells. Thus, our data indicate that maintaining low PCAF levels plays an essential role in AT-mediated cardiac protection, and PCAF inhibition represents a promising therapeutic target for attenuating cardiac remodeling after MI.

The antidepressant effect of Shexiang Baoxin Pills on myocardial infarction rats with depression may be achieved through the inhibition of the NLRP3 inflammasome pathway.

BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).

Unraveling shared molecular signatures and potential therapeutic targets linking psoriasis and acute myocardial infarction.

Psoriasis, a chronic inflammatory skin disorder, is associated with comorbidities such as acute myocardial infarction (AMI). However, the molecular mechanisms connecting these conditions are unclear. In this study, we conducted bioinformatics analyses using gene expression datasets to identify differentially expressed genes and hub genes associated with both psoriasis and AMI. Our findings emphasize the involvement of immune-related pathways in the pathogenesis of both conditions. Furthermore, we investigated the expression levels of hub genes in AMI patients and myocardial infarction (MI) mice. ELISA measurements revealed significantly higher levels of CXCL8, IL1B, S100A9, and S100A12 in the serum of AMI patients compared to normal individuals. Immunohistochemical staining of heart tissue from MI mice showed a progressive increase in the expression of CXCL8 and IL-1B as MI advanced, while S100A9 exhibited high expression at day 3 post-MI. mRNA expression analysis validated these findings. Additionally, we explored the skin lesions of psoriasis patients and found significantly higher expression of CXCL8, IL-1B, S100A9, and S100A12 in the affected skin areas compared to unaffected regions. These results highlight the consistent upregulation of hub genes in both AMI and psoriasis patients, as well as in myocardial infarction mice, underscoring their potential as reliable markers for disease diagnosis. Moreover, molecular docking simulations revealed potential interactions between simvastatin and key target proteins, suggesting a potential therapeutic avenue. Overall, our study uncovers shared molecular signatures and potential therapeutic targets, providing a foundation for future investigations targeting common pathways in psoriasis and AMI.

Protective effects of 3, 4-dihydroxybenzoic acid on myocardial infarction induced by isoproterenol in rats.

Despite considerable advances in interventions and treatment, there is a high mortality rate in patients with myocardial infarction (MI). This is the first study to investigate the protective effects of 3, 4-dihydroxybenzoic acid against isoproterenol induced MI in rats. MI was induced by isoproterenol (100-mg/kg body weight) in rats. Then, rats were treated with 3, 4-dihydroxybenzoic acid (16-mg/kg body weight) for 2 weeks. Serum creatine kinase-MB, cardiac troponin-T, cardiac troponin-I, and heart thiobarbituric acid reactive substances were significantly (p < 0.05) increased and heart superoxide dismutase and catalase activities were significantly (p < 0.05) reduced in isoproterenol-induced myocardial infarcted rats. Isoproterenol induction significantly (p < 0.05) elevated the plasma homocysteine and serum high sensitivity-C-reactive protein levels. Furthermore, an enzyme-linked immunosorbent assay, reverse transcription polymerase chain study, and immunohistochemical (IHC) staining revealed significantly (p < 0.05) elevated levels and expression of serum/myocardial nuclear factor-κB, tumor necrosis factor-alpha, interleukin-1 beta, and Interleukin-6 and significantly (p < 0.05) reduced levels/expression of serum/myocardial interleukin-10 in myocardial infarcted rats. Nevertheless, isoproterenol-induced rats treated with 3, 4-dihydroxybenzoic acid considerably (p < 0.05) attenuated all the biochemical, molecular, and IHC parameters investigated and inhibited oxidative stress and inflammation and protected the heart, through its antioxidant and anti-inflammatory mechanisms.

M1 macrophage-derived exosomes inhibit cardiomyocyte proliferation through delivering miR-155.

BACKGROUND: M1 macrophages are closely associated with cardiac injury after myocardial infarction (MI). Increasing evidence shows that exosomes play a key role in pathophysiological regulation after MI, but the role of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration remains unclear. In this study, we explored the impact of M1 macrophage-derived exosomes on cardiomyocytes regeneration in vitro and in vivo. METHODS: M0 macrophages were induced to differentiate into M1 macrophages with GM-CSF (50 ng/mL) and IFN-γ (20 ng/mL). Then M1-Exos were isolated and co-incubated with cardiomyocytes. Cardiomyocyte proliferation was detected by pH3 or ki67 staining. Quantitative real-time PCR (qPCR) was used to test the level of miR-155 in macrophages, macrophage-derived exosomes and exosome-treated cardiomyocytes. MI model was constructed and LV-miR-155 was injected around the infarct area, the proliferation of cardiomyocytes was counted by pH3 or ki67 staining. The downstream gene and pathway of miR-155 were predicted and verified by dual-luciferase reporter gene assay, qPCR and immunoblotting analysis. IL-6 (50 ng/mL) was added to cardiomyocytes transfected with miR-155 mimics, and the proliferation of cardiomyocytes was calculated by immunofluorescence. The protein expressions of IL-6R, p-JAK2 and p-STAT3 were detected by Western blot. RESULTS: The results showed that M1-Exos suppressed cardiomyocytes proliferation. Meanwhile, miR-155 was highly expressed in M1-Exos and transferred to cardiomyocytes. miR-155 inhibited the proliferation of cardiomyocytes and antagonized the pro-proliferation effect of interleukin 6 (IL-6). Furthermore, miR-155 targeted gene IL-6 receptor (IL-6R) and inhibited the Janus kinase 2(JAK)/Signal transducer and activator of transcription (STAT3) signaling pathway. CONCLUSION: M1-Exos inhibited cardiomyocyte proliferation by delivering miR-155 and inhibiting the IL-6R/JAK/STAT3 signaling pathway. This study provided new insight and potential treatment strategy for the regulation of myocardial regeneration and cardiac repair by macrophages.

M2 macrophage-derived exosomes promote angiogenesis and improve cardiac function after myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. The intercellular communication in post-infarction angiogenesis remains unclear. METHODS: In this study, we explored the role and mechanism of action of M2 macrophage-derived exosomes (M2-exos) in angiogenesis after MI. M2-exos were harvested and injected intramyocardially at the onset of MI. Two distinct endothelial cells (ECs) were cultured with M2-exos to explore the direct effects on angiogenesis. RESULTS: We showed that M2-exos improved cardiac function, reduced infarct size, and enhanced angiogenesis after MI. Moreover, M2-exos promoted angiogenesis in vitro; the molecules loaded in the vesicles were responsible for its proangiogenic effects. We further validated that higher abundance of miR-132-3p in M2-exos, which recapitulate their functions, was required for the cardioprotective effects exerted by M2-exos. Mechanistically, miR-132-3p carried by M2-exos down-regulate the expression of THBS1 through direct binding to its 3´UTR and the proangiogenic effects of miR-132-3p were largely reversed by THBS1 overexpression. CONCLUSION: Our findings demonstrate that M2-exos promote angiogenesis after MI by transporting miR-132-3p to ECs, and by binding to THBS1 mRNA directly and negatively regulating its expression. These findings highlight the role of M2-exos in cardiac repair and provide novel mechanistic understanding of intercellular communication in post-infarction angiogenesis.

LncRNA NEAT1/miR-211/IL-10 Axis Regulates Inflammation of Peripheral Blood Mononuclear Cells in Acute Myocardial Infarction.

This study aimed to explore the expression of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in patients with acute myocardial infarction (AMI) and its inflammatory regulation mechanism through miR-211/interleukin 10 (IL-10) axis.A total of 75 participants were enrolled in this study: 25 healthy people in the control group, 25 patients with stable angina pectoris (SAP) in the SAP group, and 25 patients with AMI in the AMI group. Real-time qPCR was used to detect mRNA expression levels of NEAT1, miR-211, and IL-10. The interaction between miR-211, NEAT1, and IL-10 was confirmed by dual-luciferase reporter assay, and protein expression was detected using western blot.High expression of NEAT1 in peripheral blood mononuclear cells (PBMCs) of patients with AMI was negatively related to serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), IL-6, and IL-1ß and was positively correlated with left ventricular ejection fraction (LVEF). In THP-1 cells, miR-211 was confirmed to target and inhibit IL-10 expression. NEAT1 knockdown and miR-211-mimic markedly decreased IL-10 protein levels, whereas anti-miR-211 markedly increased IL-10 protein levels. Importantly, miR-211 level was negatively related to NEAT1 and IL-10 levels, whereas IL-10 level was positively related to the level of NEAT1 expression in PBMCs of patients with AMI.LncRNA NEAT1 was highly expressed in PBMCs of patients with AMI, and NEAT1 suppressed inflammation via miR-211/IL-10 axis in PBMCs of patients with AMI.

LncRNA Peg13 Alleviates Myocardial Infarction/Reperfusion Injury through Regulating MiR-34a/Sirt1-Mediated Endoplasmic Reticulum Stress.

Myocardial infarction/reperfusion (I/R) injury significantly impacts the health of older individuals. We confirmed that the level of lncRNA Peg13 was downregulated in I/R injury. However, the detailed function of Peg13 in myocardial I/R injury has not yet been explored.To detect the function of Peg13, in vivo model of I/R injury was constructed. RT-qPCR was employed to investigate RNA levels, and Western blotting was performed to assess levels of endoplasmic reticulum stress and apoptosis-associated proteins. EdU staining was confirmed to assess the cell proliferation.I/R therapy dramatically produced myocardial injury, increased the infarct area, and decreased the amount of Peg13 in myocardial tissues of mice. In addition, hypoxia/reoxygenation (H/R) notably induced the apoptosis and promoted the endoplasmic reticulum (ER) stress of HL-1 cells, while overexpression of Peg13 reversed these phenomena. Additionally, Peg13 may increase the level of Sirt1 through binding to miR-34a. Upregulation of Peg13 reversed H/R-induced ER stress via regulation of miR-34a/Sirt1 axis.LncRNA Peg13 reduces ER stress in myocardial infarction/reperfusion injury through mediation of miR-34a/Sirt1 axis. Hence, our research might shed new lights on developing new strategies for the treatment of myocardial I/R injury.

Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.

Acute myocardial infarction (AMI) is a serious condition that occurs when part of the heart is subjected to ischemia episodes, following partial or complete occlusion of the epicardial coronary arteries. The resulting damage to heart muscle cells have a significant impact on patient's health and quality of life. About that, recent research focused on the role of the sarcoplasmic reticulum (SR) and mitochondria in the physiopathology of AMI. Moreover, SR and mitochondria get in touch each other through multiple membrane contact sites giving rise to the subcellular region called mitochondria-associated membranes (MAMs). MAMs are essential for, but not limited to, bioenergetics and cell fate. Disruption of the architecture of these regions occurs during AMI although it is still unclear the cause-consequence connection and a complete overview of the pathological changes; for sure this concurs to further damage to heart muscle. The calcium ion (Ca2+) plays a pivotal role in the pathophysiology of AMI and its dynamic signaling between the SR and mitochondria holds significant importance. In this review, we tried to summarize and update the knowledge about the roles of these organelles in AMI from a Ca2+ signaling point of view. Accordingly, we also reported some possible cardioprotective targets which are directly or indirectly related at limiting the dysfunctions caused by the deregulation of the Ca2+ signaling.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Dynamics of collagen oxidation and cross linking in regenerating and irreversibly infarcted myocardium.

In mammalian hearts myocardial infarction produces a permanent collagen-rich scar. Conversely, in zebrafish a collagen-rich scar forms but is completely resorbed as the myocardium regenerates. The formation of cross-links in collagen hinders its degradation but cross-linking has not been well characterized in zebrafish hearts. Here, a library of fluorescent probes to quantify collagen oxidation, the first step in collagen cross-link (CCL) formation, was developed. Myocardial injury in mice or zebrafish resulted in similar dynamics of collagen oxidation in the myocardium in the first month after injury. However, during this time, mature CCLs such as pyridinoline and deoxypyridinoline developed in the murine infarcts but not in the zebrafish hearts. High levels of newly oxidized collagen were still seen in murine scars with mature CCLs. These data suggest that fibrogenesis remains dynamic, even in mature scars, and that the absence of mature CCLs in zebrafish hearts may facilitate their ability to regenerate.

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels.

Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI.