Dataset Information

Extracellular vesicle-packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction.

ABSTRACT: Mounting evidence suggests that extracellular vesicles (EVs) are effective communicators in biological signalling in cardiac physiology and pathology. However, the role of EVs in cardiac injury, particularly in ischemic myocardial scenarios, has not been fully elucidated. Here, we report that acute myocardial infarction (AMI)-induced EVs can impair cardiomyocyte survival and exacerbate cardiac injury. EV-encapsulated miR-503, which is enriched during the early phase of AMI, is a critical molecule that mediates myocardial injury. Functional studies revealed that miR-503 promoted cardiomyocyte death by directly binding to peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and a mitochondrial deacetylase, sirtuin 3 (SIRT3), thereby triggering mitochondrial metabolic dysfunction and cardiomyocyte death. Mechanistically, we identified endothelial cells as the primary source of miR-503 in EVs after AMI. Hypoxia induced rapid H3K4 methylation of the promoter of the methyltransferase-like 3 gene (METTL3) and resulted in its overexpression. METTL3 overexpression evokes N6-methyladenosine (m⁶ A)-dependent miR-503 biogenesis in endothelial cells. In summary, this study highlights a novel endogenous mechanism wherein EVs aggravate myocardial injury during the onset of AMI via endothelial cell-secreted miR-503 shuttling.

SUBMITTER: Sun P

PROVIDER: S-EPMC9028097 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Extracellular vesicle-packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction.

Sun Ping P Wang Chao C Mang Ge G Xu Xiangli X Fu Shuai S Chen Jianfeng J Wang Xiaoqi X Wang Weiwei W Li Hairu H Zhao Peng P Li Yifei Y Chen Qi Q Wang Naixin N Tong Zhonghua Z Fu Xin X Lang Ying Y Duan Shasha S Liu Dongmei D Zhang Maomao M Tian Jiawei J

Clinical and translational medicine 20220401 4

Mounting evidence suggests that extracellular vesicles (EVs) are effective communicators in biological signalling in cardiac physiology and pathology. However, the role of EVs in cardiac injury, particularly in ischemic myocardial scenarios, has not been fully elucidated. Here, we report that acute myocardial infarction (AMI)-induced EVs can impair cardiomyocyte survival and exacerbate cardiac injury. EV-encapsulated miR-503, which is enriched during the early phase of AMI, is a critical molecul ...[more]

PMID: 35452193

Similar Datasets

Project description:Myocardial infarction (MI), a main cause of heart failure, leads to irreversible cardiomyocytes loss and cardiac function impairment. Current clinical treatments for MI are largely ineffective as they mostly aim to alleviate symptoms rather than repairing the injured myocardium. Thus, development of more effective therapies is compelling. This study aims to investigate whether the extracellular vesicles (EVs) carrying specific anti-apoptotic miRNA can be efficiently internalized into myocardium to achieve desired therapeutic outcomes. Methods: EVs were isolated from HEK293T cells overexpressing miRNA-21 (miR21-EVs) and identified. The RNase resistant rate of miR21-EVs was calculated by real-time PCR and compared with liposomes and polyethylenimine (PEI). Confocal laser scanning microscopy was used for visualizing the cellular internalization of miR21-EVs in primary cultured mouse neonatal cardiomyocytes (CMs), H9c2 rat cardiomyoblasts, and human umbilical vein endothelial cells (HUVECs). The effect of miR21-EVs on the expression of PDCD4, a pro-apoptotic protein that plays an important role in regulating myocardial apoptosis, was also evaluated in these three cell types by real-time PCR and Western blot analysis. In vivo, miR21-EVs was directly injected into the infarct zone following ligation of the left anterior descending of coronary artery in mice. The miR21-EVs distribution and blood vessel (capillary and arteriole) density were evaluated by immunofluorescence staining. Fluorescence in situ hybridization of miRNA-21 was also carried out to confirm the miR21-EVs distribution in vitro and in vivo. The protein level of PDCD4 in myocardium was assessed by immunohistochemical staining. The anti-apoptotic effect of miR21-EVs in cardiomyocytes and endothelial cells were measured using TUNEL staining. Four weeks after injection, the cardiac histological and functional recovery was evaluated by histochemistry staining and echocardiography, respectively. Results: In contrast to liposomes and PEI, EVs significantly inhibited miRNA-21 degradation. MiR21-EVs efficiently delivered miRNA-21 into cardiomyocytes and endothelial cells within 4 hours. Exogenous miRNA-21 in turn significantly reduced PDCD4 expression and attenuated cell apoptosis in vitro. Consistently and importantly, in a preclinical MI animal model, miRNA-21-loaded EVs effectively sent miRNA-21 into cardiomyocytes and endothelial cells, drastically inhibited cell apoptosis and led to significant cardiac function improvement. Conclusion: Our results suggest the cell-derived, genetically engineered EVs may be used therapeutically for the delivery of miRNAs for the rescue of MI and may benefit patients in the future.

Project description:BackgroundMyocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an extracellular matrix (ECM) protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown.MethodsThree microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast-macrophage co-culture model in vitro.ResultsITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast-macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages.ConclusionsITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Project description:BackgroundExposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter ≤ 10 μm (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study.ResultsShort-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio™ 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels.ConclusionsResearch on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development.

Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Dataset Information

Extracellular vesicle-packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction.

Publications

Extracellular vesicle-packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets