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.

Novel Fibrillar and Non-Fibrillar Collagens Involved in Fibrotic Scar Formation after Myocardial Infarction.

Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship.

Dynamic Changes in Ion Channels during Myocardial Infarction and Therapeutic Challenges.

In different areas of the heart, action potential waveforms differ due to differences in the expressions of sodium, calcium, and potassium channels. One of the characteristics of myocardial infarction (MI) is an imbalance in oxygen supply and demand, leading to ion imbalance. After MI, the regulation and expression levels of K+, Ca2+, and Na+ ion channels in cardiomyocytes are altered, which affects the regularity of cardiac rhythm and leads to myocardial injury. Myocardial fibroblasts are the main effector cells in the process of MI repair. The ion channels of myocardial fibroblasts play an important role in the process of MI. At the same time, a large number of ion channels are expressed in immune cells, which play an important role by regulating the in- and outflow of ions to complete intracellular signal transduction. Ion channels are widely distributed in a variety of cells and are attractive targets for drug development. This article reviews the changes in different ion channels after MI and the therapeutic drugs for these channels. We analyze the complex molecular mechanisms behind myocardial ion channel regulation and the challenges in ion channel drug therapy.

Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.

Role of deubiquitinase USP47 in cardiac function alleviation and anti-inflammatory immunity after myocardial infarction by regulating NLRP3 inflammasome-mediated pyroptotic signal pathways.

Myocardial infarction (MI) is an event of heart attack due to the formation of plaques in the interior walls of the arteries. This study is conducted to explore the role of ubiquitin-specific peptidase 47 (USP47) in cardiac function and inflammatory immunity. MI mouse models were established, followed by an appraisal of cardiac functions, infarct size, pathological changes, and USP47 and NLRP3 levels. MI cell models were established in HL-1 cells using anoxia. Levels of cardiac function-associated proteins, USP7, interferon regulatory factor 1 (IRF1), platelet factor-4 (CXCL4), pyroptotic factors, and neutrophil extracellular traps (NETs) were determined. The bindings of IRF1 to USP47 and the CXCL4 promoter and the ubiquitination of IRF1 were analyzed. USP47 was upregulated in myocardial tissues of MI mice. USP47 inhibition alleviated cardiac functions, and decreased infarct size, pro-inflammatory cytokines, NETs, NLRP3, and pyroptosis. The ubiquitination and expression levels of IRF1 were increased by silencing USP47, and IRF1 bound to the CXCL4 promoter to promote CXCL4. Overexpression of IRF1 or CXCL4 in vitro and injection of Nigericin in vivo reversed the effect of silencing USP47 on alleviating pyroptosis and cardiac functions. Collectively, USP47 stabilized IRF1 and promoted CXCL4, further promoting pyroptosis, impairing cardiac functions, and aggravating immune inflammation through NLRP3 pathways.

Optimizing cell therapy by sorting cells with high extracellular vesicle secretion.

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. Here, we utilize a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach is applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibit distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintain high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improves heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.

Neutrophil NLRP3 promotes cardiac injury following acute myocardial infarction through IL-1ß production, VWF release and NET deposition in the myocardium.

NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1ß). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3-/- mice as well as in NLRP3-/- recipient mice transfused with either WT or NLRP3-/- neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3-/- neutrophils after MI increased infarct size in NLRP3-/- mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1ß and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1ß and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.

Galanin Coordinates Macrophage-Associated Fibro-Inflammatory Response and Mitochondrial Integrity in Myocardial Infarction Reperfusion Injury.

Myocardial infarction activates an intense fibro-inflammatory reaction that is essential for cardiac remodeling and heart failure (HF). Bioactive peptide galanin plays a critical role in regulating cardiovascular homeostasis; however, its specific functional relevance in post-infarction fibro-inflammatory reprogramming remains obscure. Here, we show that galanin coordinates the fibro-inflammatory trajectory and mitochondrial integrity in post-infarction reperfusion injury. Aberrant deposition of collagen was associated with a marked increase in CD68-positive macrophage infiltration in cardiac tissue in mice subjected to myocardial ischemia/reperfusion (I/R) for 14 days compared to sham controls. Furthermore, we found that the myocardial expression level of a specific marker of M2 macrophages, CD206, was significantly down-regulated in I/R-challenged mice. In contrast, galanin treatment started during the reperfusion phase blunted the fibro-inflammatory responses and promoted the expression of CD206 in I/R-remodeled hearts. In addition, we found that the anti-apoptotic and anti-hypertrophic effects of galanin were associated with the preservation of mitochondrial integrity and promotion of mitochondrial biogenesis. These findings depict galanin as a key arbitrator of fibro-inflammatory responses to cardiac I/R injury and offer a promising therapeutic trajectory for the treatment of post-infarct cardiovascular complications.

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.

Expression characteristics of lipid metabolism-related genes and correlative immune infiltration landscape in acute myocardial infarction.

Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.

Prediction of Interactomic HUB Genes in Periodontitis With Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) risk correlates with C-reactive protein (CRP) levels, suggesting systemic inflammation is present well before AMI. Studying different types of periodontal disease (PD), extremely common in individuals at risk for AMI, has been one important research topic. According to recent research, AMI and PD interact via the systemic production of certain proinflammatory and anti-inflammatory cytokines, small signal molecules, and enzymes that control the onset and development of both disorders' chronic inflammatory reactions. This study uses machine learning to identify the interactome hub biomarker genes in acute myocardial infarction and periodontitis. METHODS: GSE208194 and GSE222883 were chosen for our research after a thorough search using keywords related to the study's goal from the gene expression omnibus (GEO) datasets. DEGs were identified from the GEOR tool, and the hub gene was identified using Cytoscape-cytohubba. Using expression values, Random Forest, Adaptive Boosting, and Naive Bayes, widgets-generated transcriptomics data, were labelled, and divided into 80/20 training and testing data with cross-validation. ROC curve, confusion matrix, and AUC were determined. In addition, Functional Enrichment Analysis of Differentially Expressed Gene analysis was performed. RESULTS: Random Forest, AdaBoost, and Naive Bayes models with 99%, 100%, and 75% AUC, respectively. Compared to RF, AdaBoost, and NB classification models, AdaBoost had the highest AUC. Categorization algorithms may be better predictors than important biomarkers. CONCLUSIONS: Machine learning model predicts hub and non-hub genes from genomic datasets with periodontitis and acute myocardial infarction.

Research of the dynamic regulatory mechanism of Compound Danshen Dripping Pills on myocardial infarction based on metabolic trajectory analysis.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease, which presents different pathophysiological changes with the prolongation of the disease. Compound danshen dripping pills (CDDP) has obvious advantages in MI treatment and widely used in the clinic. However, the current studies were mostly focused on the endpoint of CDDP intervention, lacking the dynamic attention to the disease process. It is of great value to establish a dynamic research strategy focused on the changes in pharmacodynamic substances for guiding clinical medication more precisely. PURPOSE: It is aimed to explore the dynamic regulating pattern of CDDP on MI based on metabolic trajectory analysis, and then clarify the variation characteristic biomarkers and pharmacodynamic substances in the intervention process. METHODS: The MI model was successfully prepared by coronary artery left anterior descending branch ligation, and then CDDP intervention was given for 28 days. Endogenous metabolites and the components of CDDP in serum were measured by LC/MS technique simultaneously to identify dynamic the metabolic trajectory and screen the characteristic pharmacodynamic substances at different points. Finally, network pharmacology and molecular docking techniques were used to simulate the core pharmacodynamic substances and core target binding, then validated at the genetic and protein level by Q-PCR and western blotting technology. RESULTS: CDDP performed typical dynamic regulation features on metabolite distribution, biological processes, and pharmacodynamic substances. During 1-7 days, it mainly regulated lipid metabolism and inflammation, the Phosphatidylcholine (PC(18:1(9Z/18:1(9Z)) and Sphingomyelin (SM(d18:1/23:1(9Z)), SM(d18:1/24:1(15Z)), SM(d18:0/16:1(9Z))) were the main characteristic biomarkers. Lipid metabolism was the mainly regulation pathway during 14-21 days, and the characteristic biomarkers were the Lysophosphatidylethanolamine (LysoPE(0:0/20:0), PE-NMe2(22:1(13Z)/15:0)) and Sphingomyelin (SM(d18:1/23:1(9Z))). At 28 days, in addition to inflammatory response and lipid metabolism, fatty acid metabolism also played the most important role. Correspondingly, Lysophosphatidylcholine (LysoPC(20:0/0:0)), Lysophosphatidylserine (LPS(18:0/0:0)) and Fatty acids (Linoelaidic acid) were the characteristic biomarkers. Based on the results of metabolite distribution and biological process, the characteristic pharmacodynamic substances during the intervention were further identified. The results showed that various kinds of Saponins and Tanshinones as the important active ingredients performed a long-range regulating effect on MI. And the other components, such as Tanshinol and Salvianolic acid B affected Phosphatidylcholine and Sphingomyelin through Relaxin Signaling pathway during the early intervention. Protocatechualdehyde and Rosmarinic acid affected Lysophosphatidylethanolamine and Sphingomyelin through EGFR Tyrosine kinase inhibitor resistance during the late intervention. Tanshinone IIB and Isocryptotanshinone via PPAR signaling pathway affected Lysophosphatidylcholine, Lysophosphatidylserine, and Fatty acids. CONCLUSION: The dynamic regulating pattern was taken as the entry point and constructs the dynamic network based on metabolic trajectory analysis, establishes the dynamic correlation between the drug-derived components and the endogenous metabolites, and elucidates the characteristic biomarkers affecting the changes of the pharmacodynamic indexes, systematically and deeply elucidate the pharmacodynamic substance and mechanism of CDDP on MI. It also enriched the understanding of CDDP and provided a methodological reference for the dynamic analysis of complex systems of TCM.

Macrophage and fibroblast trajectory inference and crosstalk analysis during myocardial infarction using integrated single-cell transcriptomic datasets.

BACKGROUND: Cardiac fibrosis after myocardial infarction (MI) has been considered an important part of cardiac pathological remodeling. Immune cells, especially macrophages, are thought to be involved in the process of fibrosis and constitute a niche with fibroblasts to promote fibrosis. However, the diversity and variability of fibroblasts and macrophages make it difficult to accurately depict interconnections. METHODS: We collected and reanalyzed scRNA-seq and snRNA-seq datasets from 12 different studies. Differentiation trajectories of these subpopulations after MI injury were analyzed by using scVelo, PAGA and Slingshot. We used CellphoneDB and NicheNet to infer fibroblast-macrophage interactions. Tissue immunofluorescence staining and in vitro experiments were used to validate our findings. RESULTS: We discovered two subsets of ECM-producing fibroblasts, reparative cardiac fibroblasts (RCFs) and matrifibrocytes, which appeared at different times after MI and exhibited different transcriptional profiles. We also observed that CTHRC1+ fibroblasts represent an activated fibroblast in chronic disease states. We identified a macrophage subset expressing the genes signature of SAMs conserved in both human and mouse hearts. Meanwhile, the SPP1hi macrophages were predominantly found in the early stages after MI, and cell communication analysis indicated that SPP1hi macrophage-RCFs interactions are mainly involved in collagen deposition and scar formation. CONCLUSIONS: Overall, this study comprehensively analyzed the dynamics of fibroblast and macrophage subsets after MI and identified specific subsets of fibroblasts and macrophages involved in scar formation and collagen deposition.

Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets. miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.

Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration.

Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia-reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia-reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia-reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia-reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia-reperfusion injury.

Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities.

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.

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.

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.

Inhibition of tartrate-resistant acid phosphatase 5 can prevent cardiac fibrosis after myocardial infarction.

BACKGROUND: Myocardial infarction (MI) leads to enhanced activity of cardiac fibroblasts (CFs) and abnormal deposition of extracellular matrix proteins, resulting in cardiac fibrosis. Tartrate-resistant acid phosphatase 5 (ACP5) has been shown to promote cell proliferation and phenotypic transition. However, it remains unclear whether ACP5 is involved in the development of cardiac fibrosis after MI. The present study aimed to investigate the role of ACP5 in post-MI fibrosis and its potential underlying mechanisms. METHODS: Clinical blood samples were collected to detect ACP5 concentration. Myocardial fibrosis was induced by ligation of the left anterior descending coronary artery. The ACP5 inhibitor, AubipyOMe, was administered by intraperitoneal injection. Cardiac function and morphological changes were observed on Day 28 after injury. Cardiac CFs from neonatal mice were extracted to elucidate the underlying mechanism in vitro. The expression of ACP5 was silenced by small interfering RNA (siRNA) and overexpressed by adeno-associated viruses to evaluate its effect on CF activation. RESULTS: The expression of ACP5 was increased in patients with MI, mice with MI, and mice with Ang II-induced fibrosis in vitro. AubipyOMe inhibited cardiac fibrosis and improved cardiac function in mice after MI. ACP5 inhibition reduced cell proliferation, migration, and phenotypic changes in CFs in vitro, while adenovirus-mediated ACP5 overexpression had the opposite effect. Mechanistically, the classical profibrotic pathway of glycogen synthase kinase-3ß (GSK3ß)/ß-catenin was changed with ACP5 modulation, which indicated that ACP5 had a positive regulatory effect. Furthermore, the inhibitory effect of ACP5 deficiency on the GSK3ß/ß-catenin pathway was counteracted by an ERK activator, which indicated that ACP5 regulated GSK3ß activity through ERK-mediated phosphorylation, thereby affecting ß-catenin degradation. CONCLUSION: ACP5 may influence the proliferation, migration, and phenotypic transition of CFs, leading to the development of myocardial fibrosis after MI through modulating the ERK/GSK3ß/ß-catenin signaling pathway.

Modified mRNA-Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling.

Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. The success of modRNA-based COVID-19 vaccines has demonstrated that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases, including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options, and MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and mitigates cardiac dysfunction. However, it remains unclear whether early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. We hypothesized that CCN5 would alleviate the adverse effects of myocardial infarction (MI) through its anti-fibrotic properties under stress conditions. To induce the rapid expression of CCN5, ModRNA-CCN5 was synthesized and administrated directly into the myocardium in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: (1) preventive intervention and (2) therapeutic intervention. Functional analyses, including echocardiography and magnetic resonance imaging (MRI), along with molecular assays, demonstrated that modRNA-mediated CCN5 gene transfer significantly attenuated cardiac fibrosis and improved cardiac function in both preventive and therapeutic models, without causing left ventricular rupture or any adverse cardiac remodeling. In conclusion, early intervention in CF by ModRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure.