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Pharmaceutical Biology Dec 2022Therapeutic lymphangiogenesis is a new treatment for cardiovascular diseases. Our previous study showed M2b macrophages can alleviate myocardial ischaemia/reperfusion...
CONTEXT
Therapeutic lymphangiogenesis is a new treatment for cardiovascular diseases. Our previous study showed M2b macrophages can alleviate myocardial ischaemia/reperfusion injury (MI/RI). However, the relation between M2b macrophages and lymphangiogenesis is not clear.
OBJECTIVE
To investigate the effects of M2b macrophages on lymphangiogenesis after MI/RI.
MATERIALS AND METHODS
Forty male Sprague-Dawley (SD) rats were randomized into Sham operation group (control, = 8), MI/RI group ( = 16) and M2b macrophage transplantation group ( = 16). M2b macrophages (1 × 10) in 100 μL of normal saline or the same volume of vehicle was injected into the cardiac ischaemic zone. Two weeks later, echocardiography and lymphatic counts were performed, and the extent of myocardial fibrosis and the expression of vascular endothelial growth factor C (VEGFC) and VEGF receptor 3 (VEGFR3) were determined. lymphatic endothelial cells (LECs) were cultured with M2b macrophages for 6-24 h, and the proliferation, migration and tube formation of the LECs were assessed.
RESULTS
M2b macrophage transplantation increased the level of lymphangiogenesis 2.11-fold, reduced 4.42% fibrosis, improved 18.65% left ventricular ejection fraction (LVEF) and upregulated the expressions of VEGFC and VEGFR3. M2b macrophage increased the proliferation, migration, tube formation and VEGFC expression of LECs. M2b macrophage supernatant upregulated VEGFR3 expression of LECs.
DISCUSSION AND CONCLUSIONS
Our study shows that M2b macrophages can promote lymphangiogenesis to reduce myocardial fibrosis and improve heart function, suggesting the possible use of M2b macrophage for myocardial protection therapy.
Topics: Animals; Cell Movement; Cell Proliferation; Disease Models, Animal; Echocardiography; Endothelial Cells; Fibrosis; Lymphangiogenesis; Macrophages; Male; Myocardial Reperfusion Injury; Random Allocation; Rats; Rats, Sprague-Dawley; Stroke Volume; Ventricular Function, Left
PubMed: 35188856
DOI: 10.1080/13880209.2022.2033798 -
International Journal of Molecular... Jan 2022Coronary artery disease remains the leading cause of death. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting... (Review)
Review
Coronary artery disease remains the leading cause of death. Acute myocardial infarction (MI) is characterized by decreased blood flow to the coronary arteries, resulting in cardiomyocytes death. The most effective strategy for treating an MI is early and rapid myocardial reperfusion, but restoring blood flow to the ischemic myocardium can induce further damage, known as ischemia-reperfusion (IR) injury. Novel therapeutic strategies are critical to limit myocardial IR injury and improve patient outcomes following reperfusion intervention. miRNAs are small non-coding RNA molecules that have been implicated in attenuating IR injury pathology in pre-clinical rodent models. In this review, we discuss the role of miR-1 and miR-21 in regulating myocardial apoptosis in ischemia-reperfusion injury in the whole heart as well as in different cardiac cell types with special emphasis on cardiomyocytes, fibroblasts, and immune cells. We also examine therapeutic potential of miR-1 and miR-21 in preclinical studies. More research is necessary to understand the cell-specific molecular principles of miRNAs in cardioprotection and application to acute myocardial IR injury.
Topics: Animals; Gene Expression Regulation; Genetic Therapy; Humans; MicroRNAs; Myocardial Reperfusion Injury; Translational Science, Biomedical
PubMed: 35163436
DOI: 10.3390/ijms23031512 -
Journal of Cardiovascular Translational... Oct 2023Ischemic cardiomyopathy is treated mainly with thrombolytic drugs, percutaneous coronary intervention, and coronary artery bypass grafting to recanalize blocked vessels.... (Review)
Review
Ischemic cardiomyopathy is treated mainly with thrombolytic drugs, percutaneous coronary intervention, and coronary artery bypass grafting to recanalize blocked vessels. Myocardial ischemia-reperfusion injury (MIRI) is an unavoidable complication of obstructive revascularization. Compared with those of myocardial ischemic injury, few effective therapeutic options are available for MIRI treatment. The pathophysiological mechanisms of MIRI involve the inflammatory response, the immune response, oxidative stress, apoptosis, intracellular Ca overload, and cardiomyocyte energy metabolism. These mechanisms exacerbate MIRI. Mesenchymal stem cell-derived exosomes (MSC-EXOs) can alleviate MIRI through these mechanisms and, to some extent, prevent the limitations caused by direct MSC administration. Therefore, using MSC-EXOs instead of MSCs to treat MIRI is a potentially beneficial cell-free treatment strategy. In this review, we describe the mechanism of action of MSC-EXO-derived noncoding RNAs in the treatment of MIRI and discuss the advantages and limitations of this strategy, as well as possible future research directions.
Topics: Humans; Myocardial Reperfusion Injury; Myocytes, Cardiac; Apoptosis; MicroRNAs; Mesenchymal Stem Cells; Exosomes
PubMed: 37286924
DOI: 10.1007/s12265-023-10401-w -
Redox Biology Apr 2023Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and...
Cysteine hydropersulfide reduces lipid peroxidation and protects against myocardial ischaemia-reperfusion injury - Are endogenous persulfides mediators of ischaemic preconditioning?
Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and oxidant properties, modulates redox-dependent signal transduction and has been shown to mitigate oxidative stress. However, its functional relevance in the setting of myocardial ischaemia-reperfusion injury (IRI) remains unknown. The present study was undertaken to (1) study the dynamics of production and consumption of persulfides under normoxic and hypoxic conditions in the heart, and (2) determine whether exogenous administration of the CysSSH donor, cysteine trisulfide (Cys-SSS-Cys) at the onset of reperfusion rescues functional impairment and myocardial damage by interfering with lipid peroxidation. Utilising a well-established ex vivo Langendorff murine model, we here demonstrate that endogenous tissue concentrations of CysSSH are upregulated when oxygen supply is compromised (global myocardial ischaemia) and rapidly restored to baseline levels upon reperfusion, suggestive of active regulation. In a separate set of experiments, exogenous administration of Cys-SSS-Cys for 10 min at the onset of reperfusion was found to decrease malondialdehyde (MDA) concentrations, formation of 4-hydroxynonenal (4-HNE) protein adducts and rescue the heart from injury. Cys-SSS-Cys also restored post-ischaemic cardiac function, improving both coronary flow and left ventricular developed pressure (LVDP). Taken together, these results support the notion that endogenous CysSSH plays an important role as a "redox preconditioning" agent to combat the oxidative insult in myocardial IRI.
Topics: Mice; Animals; Myocardial Reperfusion Injury; Lipid Peroxidation; Cysteine; Ischemic Preconditioning; Myocardium; Ischemic Preconditioning, Myocardial; Mammals
PubMed: 36657187
DOI: 10.1016/j.redox.2023.102605 -
Cardiovascular Journal of Africa 2020The aim of this study was to evaluate the temporal relationship between mitochondrial oxidative phosphorylation and mitophagy in rat hearts subjected to...
AIM
The aim of this study was to evaluate the temporal relationship between mitochondrial oxidative phosphorylation and mitophagy in rat hearts subjected to ischaemia/reperfusion. Measurements were made at specific points during the experimental protocol (snapshot approach) and by assessments of mitophagic flux, using chloroquine pre-treatment.
METHODS
Isolated working rat hearts were subjected to 25 or 30 minutes of global ischaemia/10 minutes of reperfusion. Half of each group received chloroquine (10 mg/kg, intraperitoneally) one hour before experimentation. Mitochondria were isolated after stabilisation, ischaemia and reperfusion, and oxidative phosphorylation was measured polarographically. Mitochondrial mitophagy markers were detected by Western blot analysis.
RESULTS
Mitochondrial oxygen uptake (state 3) and oxidative phosphorylation rate were reduced by ischaemia and increased by reperfusion. Chloroquine pre-treatment increased both parameters. Using a snapshot approach, exposure to ischaemia ± reperfusion had little effect on mitochondrial PINK1, Parkin and p62/SQSTM1 expression. Ischaemia reduced Rab9 expression, and reperfusion upregulated the phosphor DRP1, phosphor/total DRP1 ratio and Rab9 levels. Chloroquine significantly reduced PINK1, p62/SQSTM1, Rab9 and particularly Parkin expression during reperfusion, without an effect on mitochondrial total and phospho DRP1 levels.
CONCLUSIONS
Ischaemia/reperfusion-induced changes in mitochondrial oxidative phosphorylation function occurred concomitantly with changes in mitophagic flux. Pre-treatment with chloroquine profoundly affected mitochondrial function as well as the pattern of mitophagy during ischaemia/reperfusion.
Topics: Animals; Chloroquine; Disease Models, Animal; Dynamins; Isolated Heart Preparation; Male; Mitochondria, Heart; Mitophagy; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidative Phosphorylation; Phosphorylation; Protein Kinases; Rats, Wistar; Sequestosome-1 Protein; Signal Transduction; Time Factors; Ubiquitin-Protein Ligases; rab GTP-Binding Proteins
PubMed: 31995116
DOI: 10.5830/CVJA-2019-067 -
Redox Biology Nov 2023Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective...
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
Topics: Mice; Animals; Myocytes, Cardiac; Epigenesis, Genetic; Adenosine; Insulin-Like Growth Factor I; Positron Emission Tomography Computed Tomography; Ischemia; Myocardial Reperfusion Injury; Mice, Knockout; Apoptosis; Reperfusion; DNA; Glucose
PubMed: 37725888
DOI: 10.1016/j.redox.2023.102884 -
European Review For Medical and... Jun 2022Myocardial ischemia-reperfusion injury (MIRI) is the main cause of death from ischemic heart diseases. Stanniocalcin 1 (STC1) has a potential therapeutic effect on MIRI....
OBJECTIVE
Myocardial ischemia-reperfusion injury (MIRI) is the main cause of death from ischemic heart diseases. Stanniocalcin 1 (STC1) has a potential therapeutic effect on MIRI. The purpose of this study is to investigate the effect of STC1 on inflammation and apoptosis of myocardium in MIRI.
MATERIALS AND METHODS
We used rats to make ischemia-reperfusion (I/R) models and determined the efficiency of modeling by 2, 3, 5-triphenyl tetrazolium chloride staining, echocardiography, and lactate dehydrogenase detection. We injected subcutaneously recombinant human STC1 (2.5 μg/kg, 5 μg/kg) into rats daily one week before modeling to detect the effect of STC1 pretreatment on inflammation and apoptosis of rat myocardial cells. In addition, we cultured rat myocardial cell lines (H9c2 cells) to investigate the effect of STC1 on myocardial cells.
RESULTS
The cardiac function and structure of I/R rats were obviously destroyed. After treating rats with STC1, we found that the cardiac function and structure of the rats were significantly improved. In addition, STC1 reduced the expression of inflammatory factors and apoptosis levels in rat myocardium. Stimulation of STC1 also improved the viability of H9c2 cells in vitro.
CONCLUSIONS
Therefore, STC1 can alleviate MIRI by inhibiting inflammation and apoptosis. It indicated that STC1 may have a potential therapeutic effect on MIRI.
Topics: Animals; Apoptosis; Glycoproteins; Inflammation; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats
PubMed: 35776032
DOI: 10.26355/eurrev_202206_29070 -
International Journal of Medical... 2022Reperfusion injury following myocardial ischemia remained a challenge for optimal treatment of myocardial infarction. Ginsenosides Rb (G-Rb), the primary components of... (Review)
Review
Reperfusion injury following myocardial ischemia remained a challenge for optimal treatment of myocardial infarction. Ginsenosides Rb (G-Rb), the primary components of ginsenoside, have been reported to exert cardioprotective effects via numerous mechanisms. G-Rb1 mediate cardioprotective effects via various signaling pathways, including mitochondrial apoptotic pathway, PI3K/Akt/mTOR, HIF-1α and GRF91, RhoA, p38α MAPK, and eNOS. G-Rb2 activates the SIRT-1 pathway, while G-Rb3 promotes both JNK-mediated NF-κB and PERK/Nrf2/HMOX1. Generally, ginsenosides Rb1, 2, and 3 modulates oxidative stress, inflammation, and apoptosis, contributing to the improvement of structural, functional and biochemical parameters. In conclusion, G-Rb, particularly G-Rb1, have vast potential as a supplement in attenuating reperfusion injury. Translation into a clinical trial is warranted to confirm the beneficial effects of G-Rb.
Topics: Animals; Apoptosis; Cardiotonic Agents; Ginsenosides; Inflammation; Myocardial Reperfusion Injury; Oxidative Stress; Signal Transduction
PubMed: 34975299
DOI: 10.7150/ijms.64984 -
JACC. Cardiovascular Imaging Sep 2021
Topics: Electrocardiography; Humans; Myocardial Reperfusion; Percutaneous Coronary Intervention; Predictive Value of Tests; Reperfusion Injury; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 34023265
DOI: 10.1016/j.jcmg.2021.04.007 -
Reviews in Cardiovascular Medicine Jan 2022Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Timely reperfusion with primary percutaneous coronary intervention (PPCI)... (Review)
Review
Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Timely reperfusion with primary percutaneous coronary intervention (PPCI) remains the gold standard in patients presenting with ST-segment elevation myocardial infarction (STEMI), limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving clinical outcomes. Despite this, a significant proportion of STEMI patients develop post-infarct heart failure. We review the current understanding and up-to-date evidence base for therapeutic intervention of ischaemia-reperfusion injury (IRI), a combination of myocardial ischaemia secondary to acute coronary occlusion and reperfusion injury leading to further myocardial injury and cell death. Multiple treatment modalities have been shown to be cardioprotective and reduce IRI in experimental animal models. Recent phase II/III randomised controlled trials (RCT) have assessed multiple cardioprotective strategies ranging from ischaemic conditioning, therapeutic hypothermia and hyperoxaemia to pharmacological therapies. While several therapies have been shown to reduce infarct size in animal models or proof-of-concept studies, many larger scale trial results have proven inconsistent and disappointing. Hard clinical outcomes remain elusive. We discuss potential reasons for the difficulties in translation to clinical practice.
Topics: Animals; Coronary Occlusion; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 35092215
DOI: 10.31083/j.rcm2301023