RÉSUMÉ
Clinical efficacy and mechanism of Qishen Yiqi Dripping Pills(QSYQ) have been well researched, but the compatibility mechanism underlying its therapeutic effect still requires further analysis. This study aims to explore the compatibility mechanism of QSYQ in treating myocardial ischemia. UPLC-Q-Exactive Orbitrap-MS technique was used to obtain the absorbed blood components of QSYQ. Target proteins of the absorbed components were collected and screened using TCMSP, TCMIP, and SwissTargetPrediction databases. Disease proteins related to myocardial ischemia were obtained through GeneCards, OMIM, and DisGeNET databases. Core targets and core components were obtained using online plotting software Venny 2.1.0, STRING, and Cytoscape 3.9.1 software. David database was used for GO functional annotation and KEGG pathway enrichment of core targets, obtaining the main pathways of QSYQ in treating myocardial ischemia and drawing visualized network diagrams. The compatibility mechanism was analyzed based on "component-target", "drug-pathway", and "PI3K-AKT" characteristic pathways, and molecular docking was used for validation. This study obtained 42 absorbed blood components of QSYQ, 556 component targets, 1 980 disease targets, 69 core targets, and 15 core components. QSYQ can exert therapeutic effects on myocardial ischemia by regulating proteins such as MAPK1, RELA, SRC, JUN, and STAT3, acting on signaling pathways such as HIF-1, PI3K-AKT, Toll-like, MAPK, VEGF, etc. The interaction network diagrams of "component-target" and "drug-pathway" preliminarily elucidated the synergy among the four drugs in this prescription at the level of targets and pathways. The PI3K-AKT characteristic pathway indicated that the sovereign drug Huangqi(Astragali Radix) and minister drug Danshen(Salviae Miltiorrhizae Radix et Rhizoma) could regulate most targets in this pathway, while the assistant drug Sanqi(Notoginseng Radix et Rhizoma) cooperated with Huangqi and Danshen on IL6 and AKT proteins, and the envoy drug Jiangxiang(Dalbergiae Odoriferae Lignum) acted on AKT and RXRA proteins, with all drugs acting synergistically on proteins such as AKT, RXRA, NFKB to regulate cell survival and promote angiogenesis. Molecular docking indicated that hydrogen bonding and hydrophobic interactions might be the main forms of action, also validating the distribution of binding energy of the PI3K-AKT signaling pathway. This study analyzed the compatibility connotation of QSYQ from multiple dimensions including drugs, components, targets, and pathways, providing reference basis for the study of the mechanism of action and compatibility rules of QSYQ.
Sujet(s)
Médicaments issus de plantes chinoises , Ischémie myocardique , Pharmacologie des réseaux , Médicaments issus de plantes chinoises/composition chimique , Médicaments issus de plantes chinoises/pharmacologie , Ischémie myocardique/traitement médicamenteux , Ischémie myocardique/métabolisme , Ischémie myocardique/physiopathologie , Humains , Chromatographie en phase liquide à haute performance , Spectrométrie de masse , Transduction du signal/effets des médicaments et des substances chimiques , Simulation de docking moléculaireRÉSUMÉ
The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.
Sujet(s)
Lectines de type C , Macrophages , Souris de lignée C57BL , Ischémie myocardique , Phénanthrènes , Transduction du signal , Animaux , Lectines de type C/génétique , Lectines de type C/métabolisme , Mâle , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Macrophages/immunologie , Ischémie myocardique/traitement médicamenteux , Ischémie myocardique/immunologie , Ischémie myocardique/génétique , Ischémie myocardique/métabolisme , Phénanthrènes/pharmacologie , HumainsRÉSUMÉ
A relevant role of osteopontin (OPN) and gremlin 1 (Grem1) in regulating cardiac tissue remodeling and formation of heart failure (HF) are documented, with the changes of OPN and Grem1 levels in blood plasma due to acute ischemia, ischemic heart disease-induced advanced HF or dilatative cardiomyopathy being the primary focus in most of these studies. However, knowledge on the early OPN and Grem1 proteins expression changes within cardiomyocytes during remodeling due to chronic ischemia remains insufficient. The aim of this study was to determine the OPN and Grem1 proteins expression changes in human cardiomyocytes at different stages of ischemic HF. A semi-quantitative immunohistochemical analysis was performed in 105 myocardial tissue samples obtained from the left cardiac ventricles. Increased OPN immunostaining intensity was already detected in the stage A HF group, compared to the control group (p < 0.001), and continued to increase in the stage B HF (p < 0.001), achieving the peak of immunostaining in the stages C/D HF group (p < 0.001). Similar data of Grem1 immunostaining intensity changes in cardiomyocytes were documented. Significantly positive correlations were detected between OPN, Grem1 expression in cardiomyocytes and their diameter as well as the length, in addition to positive correlation between OPN and Grem1 expression changes within cardiomyocytes. These novel findings suggest that OPN and Grem1 contribute significantly to reorganization of cellular geometry from the earliest stage of cardiomyocyte remodeling, providing new insights into the ischemic HF pathogenesis.
Sujet(s)
Défaillance cardiaque , Protéines et peptides de signalisation intercellulaire , Ischémie myocardique , Myocytes cardiaques , Ostéopontine , Ostéopontine/métabolisme , Ostéopontine/génétique , Myocytes cardiaques/métabolisme , Myocytes cardiaques/anatomopathologie , Humains , Défaillance cardiaque/métabolisme , Défaillance cardiaque/anatomopathologie , Mâle , Protéines et peptides de signalisation intercellulaire/métabolisme , Protéines et peptides de signalisation intercellulaire/génétique , Ischémie myocardique/métabolisme , Ischémie myocardique/anatomopathologie , Adulte d'âge moyen , Femelle , Sujet âgéRÉSUMÉ
Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors.
Sujet(s)
Inhibiteurs de la dipeptidyl-peptidase IV , Modèles animaux de maladie humaine , Fibrose , Insuline , Ischémie myocardique , Myocarde , Transduction du signal , Phosphate de sitagliptine , Animaux , Phosphate de sitagliptine/pharmacologie , Phosphate de sitagliptine/usage thérapeutique , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacologie , Inhibiteurs de la dipeptidyl-peptidase IV/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiques , Insuline/métabolisme , Ischémie myocardique/métabolisme , Ischémie myocardique/traitement médicamenteux , Ischémie myocardique/anatomopathologie , Suidae , Myocarde/métabolisme , Myocarde/anatomopathologie , Maladie chroniqueRÉSUMÉ
ß2 adrenergic receptor (ß2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged ß2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6â¯J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30â¯mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased ß2AR levels and decreased ß2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and ß-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between ß-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of ß2AR to improve CHF.
Sujet(s)
Ginsénosides , Défaillance cardiaque , Ischémie myocardique , Protéines proto-oncogènes c-mdm2 , Récepteurs bêta-2 adrénergiques , Ubiquitination , bêta-Arrestine 2 , Animaux , Mâle , Souris , Rats , bêta-Arrestine 2/métabolisme , Lignée cellulaire , Modèles animaux de maladie humaine , Ginsénosides/pharmacologie , Défaillance cardiaque/traitement médicamenteux , Défaillance cardiaque/métabolisme , Souris de lignée C57BL , Ischémie myocardique/métabolisme , Ischémie myocardique/traitement médicamenteux , Protéines proto-oncogènes c-mdm2/métabolisme , Récepteurs bêta-2 adrénergiques/métabolisme , Ubiquitination/effets des médicaments et des substances chimiquesRÉSUMÉ
Long-term treatment of myocardial infarction is challenging despite medical advances. Tissue engineering shows promise for MI repair, but implantation complexity and uncertain outcomes pose obstacles. microRNAs regulate genes involved in apoptosis, angiogenesis, and myocardial contraction, making them valuable for long-term repair. In this study, we find downregulated miR-199a-5p expression in MI. Intramyocardial injection of miR-199a-5p into the infarcted region of male rats revealed its dual protective effects on the heart. Specifically, miR-199a-5p targets AGTR1, diminishing early oxidative damage post-myocardial infarction, and MARK4, which influences long-term myocardial contractility and enhances cardiac function. To deliver miR-199a-5p efficiently and specifically to ischemic myocardial tissue, we use CSTSMLKAC peptide to construct P-MSN/miR199a-5p nanoparticles. Intravenous administration of these nanoparticles reduces myocardial injury and protects cardiac function. Our findings demonstrate the effectiveness of P-MSN/miR199a-5p nanoparticles in repairing MI through enhanced contraction and anti-apoptosis. miR199a-5p holds significant therapeutic potential for long-term repair of myocardial infarction.
Sujet(s)
microARN , Infarctus du myocarde , Nanoparticules , microARN/génétique , microARN/métabolisme , microARN/administration et posologie , Animaux , Infarctus du myocarde/génétique , Mâle , Rats , Nanoparticules/administration et posologie , Nanoparticules/composition chimique , Rat Sprague-Dawley , Apoptose/effets des médicaments et des substances chimiques , Myocarde/métabolisme , Myocarde/anatomopathologie , Modèles animaux de maladie humaine , Contraction myocardique/effets des médicaments et des substances chimiques , Administration par voie intraveineuse , Ischémie myocardique/génétique , Ischémie myocardique/thérapie , Ischémie myocardique/métabolismeRÉSUMÉ
Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.
Sujet(s)
Cardiomyopathies diabétiques , Métabolisme énergétique , Mitochondries du myocarde , Ischémie myocardique , Stress oxydatif , Humains , Mitochondries du myocarde/métabolisme , Mitochondries du myocarde/anatomopathologie , Animaux , Cardiomyopathies diabétiques/métabolisme , Cardiomyopathies diabétiques/physiopathologie , Cardiomyopathies diabétiques/anatomopathologie , Cardiomyopathies diabétiques/étiologie , Ischémie myocardique/métabolisme , Ischémie myocardique/physiopathologie , Ischémie myocardique/anatomopathologie , Dynamique mitochondriale , Mitophagie , Espèces réactives de l'oxygène/métabolisme , Myocytes cardiaques/métabolisme , Myocytes cardiaques/anatomopathologie , Transduction du signalRÉSUMÉ
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.
Sujet(s)
Stress du réticulum endoplasmique , Galectine -3 , Obésité , Animaux , Galectine -3/métabolisme , Obésité/métabolisme , Obésité/complications , Mâle , Rats , Humains , Pectine/pharmacologie , Adulte d'âge moyen , Infarctus du myocarde/métabolisme , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/complications , Femelle , Fibrose , Rat Wistar , Ischémie myocardique/métabolisme , Ischémie myocardique/anatomopathologie , Phénylbutyrates/pharmacologie , Autophagie , Myocarde/métabolisme , Myocarde/anatomopathologie , Galectines/métabolisme , Sujet âgé , Protéines du sang/métabolismeSujet(s)
Assemblage et désassemblage de la chromatine , Régime cétogène , Mitochondries du myocarde , Ischémie myocardique , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes , Animaux , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/métabolisme , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/génétique , Ischémie myocardique/métabolisme , Ischémie myocardique/génétique , Ischémie myocardique/physiopathologie , Mitochondries du myocarde/métabolisme , Mitochondries du myocarde/anatomopathologie , Transcription génétique , Souris , Modèles animaux de maladie humaine , Mâle , HumainsRÉSUMÉ
Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17 days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP+ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17 days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.
Sujet(s)
Transplantation de moelle osseuse , Modèles animaux de maladie humaine , Cellules endothéliales , Rats transgéniques , Animaux , Mâle , Cellules endothéliales/métabolisme , Cellules endothéliales/anatomopathologie , Femelle , Néovascularisation physiologique , Ischémie myocardique/anatomopathologie , Ischémie myocardique/métabolisme , Ischémie myocardique/physiopathologie , Cellules de la moelle osseuse/métabolisme , Circulation coronarienne , Myocarde/anatomopathologie , Myocarde/métabolisme , Rats , Rat Sprague-Dawley , TranscriptomeRÉSUMÉ
MicroRNA and mitofusin-2 (Mfn2) play an important role in the myocardial apoptosis induced by acute myocardial infarction (AMI). However, the target relationship and underlying mechanism associated with interorganelle interaction between endoplasmic reticulum (ER) and mitochondria under ischemic condition is not completely clear. MI-induced injury, Mfn2 expression, Mfn2-mediated mitochondrial function and ER stress, and target regulation by miRNA-15b (miR-15b) were evaluated by animal MI and cellular hypoxic models with advanced molecular techniques. The results confirmed that Mfn2 was down-regulated and miR-15b was up-regulated upon the target binding profile under ischemic/hypoxic condition. Our data showed that miR-15b caused cardiac apoptotic injury that was reversed by rAAV9-anti-miR-15b or AMO-15b. The damage effect of miR-15b on Mfn2 expression and mitochondrial function was observed and rescued by rAAV9-anti-miR-15b or AMO-15b. The targeted regulation of miR-15b on Mfn2 was verified by luciferase reporter and microRNA-masking. Importantly, miR-15b-mediated Mfn2 suppression activated PERK/CHOP pathway, by which leads to ER stress and mitochondrial dysfunction, and cardiac apoptosis eventually. In conclusion, our research, for the first time, revealed the missing molecular link in Mfn2 and apoptosis and elucidated that pro-apoptotic miR-15b plays crucial roles during the pathogenesis of AMI through down-regulation of Mfn2 and activation of PERK-mediated ER stress. These findings may provide an opportunity to develop new therapies for prophylaxis and treatment of ischemic heart disease.
Sujet(s)
dGTPases , microARN , microARN/génétique , microARN/métabolisme , Animaux , dGTPases/génétique , dGTPases/métabolisme , Mâle , eIF-2 Kinase/métabolisme , eIF-2 Kinase/génétique , eIF-2 Kinase/antagonistes et inhibiteurs , Transduction du signal/physiologie , Ischémie myocardique/métabolisme , Ischémie myocardique/génétique , Ischémie myocardique/anatomopathologie , Souris , Stress du réticulum endoplasmique/physiologie , Stress du réticulum endoplasmique/génétique , Apoptose , Souris de lignée C57BLRÉSUMÉ
Myocardial ischemia (MI) is a significant contributor to ischemic heart diseases like angina pectoris and myocardial infarction. Reactive oxygen species produced during MI can trigger lipid peroxidation, damaging cell structure and function. Salvia miltiorrhiza (SM) has been widely used clinically in the treatment of cardiovascular diseases. However, in the process of rooting, the aboveground parts of this plant are usually discarded by tons. To make better use of these plant resources, the phenolic acids extracted and purified from the aerial part of SM were studied and chemically transformed, and the potential protective effect and possible mechanism of salvianolic acids containing a higher content of salvianolic acid A on MI were obtained. The transformed products of SM stem-leaves total phenolic acids with 8.16â¯% salvianolic acid A showed a better protective effect on the isoproterenol (ISO)-induced acute MI injury rat model. It can improve ST segment changes and has good antioxidant, anti-inflammatory and anticoagulant effects. In addition, the dysbiosis of gut microbiota and the related metabolic levels of short chain fatty acids (SCFAs), phenylalanine and glycerophospholipids were improved. This was achieved by reducing the abundance of Bacteroides, Faecalibaculum, and L-phenylalanine levels. In addition, the abundance of probiotics in Butyricoccus, Roseburia, and norank_f_Eubacterium_coprostanoligenes_group, as well as the contents of propionic acid and isobutyric acid, LPCs and PCs were increased. In conclusion, total phenolic acids of SM stem-leaves showed protective effects against ISO-induced rats, especially the strongest effect after conversion, which is a new option for the prevention and treatment of MI.
Sujet(s)
Microbiome gastro-intestinal , Hydroxybenzoates , Ischémie myocardique , Tiges de plante , Rat Sprague-Dawley , Salvia miltiorrhiza , Salvia miltiorrhiza/composition chimique , Animaux , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Hydroxybenzoates/pharmacologie , Hydroxybenzoates/isolement et purification , Mâle , Tiges de plante/composition chimique , Ischémie myocardique/métabolisme , Ischémie myocardique/traitement médicamenteux , Rats , Feuilles de plante , Métabolome/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , DysbioseRÉSUMÉ
In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis.
Sujet(s)
Acide arachidonique , Ferroptose , Ischémie myocardique , Humains , Acide arachidonique/métabolisme , Ischémie myocardique/métabolisme , Ischémie myocardique/épidémiologie , Ischémie myocardique/prévention et contrôle , Ischémie myocardique/traitement médicamenteux , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Appréciation des risques , Comorbidité , Facteurs de risque , Myocarde/métabolisme , Myocarde/anatomopathologie , Transduction du signal , Cardiomyopathies diabétiques/métabolisme , Cardiomyopathies diabétiques/prévention et contrôle , Cardiomyopathies diabétiques/épidémiologie , Diabète/épidémiologie , Diabète/métabolisme , Diabète/traitement médicamenteux , Peroxydation lipidique/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. OBJECTIVE: To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.
Sujet(s)
Monoxyde d'azote , Animaux , Concentration en ions d'hydrogène , Monoxyde d'azote/métabolisme , Mâle , Rats , Rat Wistar , Nitric oxide synthase type III/métabolisme , Myocytes cardiaques/métabolisme , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/anatomopathologie , Lésion de reperfusion myocardique/métabolisme , Lésion de reperfusion myocardique/anatomopathologie , Lésion de reperfusion myocardique/prévention et contrôle , Lésion de reperfusion myocardique/traitement médicamenteux , L-NAME/pharmacologie , Protéines proto-oncogènes c-akt/métabolisme , Nitric oxide synthase type II/métabolisme , Potentiel de membrane mitochondriale/effets des médicaments et des substances chimiques , Ischémie myocardique/métabolisme , Ischémie myocardique/anatomopathologie , Nitric oxide synthase/métabolismeRÉSUMÉ
Noninvasive and real-time optical detection of cardiac hemodynamics dysfunction during myocardial ischemia remains challenging. In this study, we developed a near-infrared spectroscopy device to monitor rats' myocardial hemodynamics. The well-designed system can accurately reflect the hemodynamics changes by the classic upper limb ischemia test. Systemic hypoxia by disconnecting to the ventilator and cardiac ischemia by coronary artery slipknot ligation was conducted to monitor myocardial hemodynamics. When systemic hypoxia occurred, ΔHbR and ΔtHb increased significantly, whereas ΔHbO decreased rapidly. When coronary blood flow was obstructed by slipknots, cardiothoracic ΔHbO immediately begins to decline, while ΔHbR also significantly increases. Simultaneously, SpO2 did not show any obvious changes during myocardial ischemia, while SpO2 decreased significantly during systemic hypoxia. These results demonstrated that cardiothoracic hemodynamics stemmed from myocardial ischemia. This pilot study demonstrated the practicality of noninvasive, low-cost optical monitoring for cardiac oxygenation dysfunction in rats.
Sujet(s)
Hémodynamique , Ischémie myocardique , Rat Sprague-Dawley , Spectroscopie proche infrarouge , Animaux , Projets pilotes , Rats , Ischémie myocardique/physiopathologie , Ischémie myocardique/imagerie diagnostique , Ischémie myocardique/métabolisme , Mâle , Maladie aigüe , Monitorage de l'hémodynamique/instrumentation , Monitorage de l'hémodynamique/méthodesRÉSUMÉ
Circular RNAs (circRNAs) are a type of single-stranded RNA that forms a covalently closed continuous loop. Its structure, stability, properties, and cell- and tissue-specificity have gained considerable recognition in the research and clinical sectors, as its role has been observed in different diseases, such as cardiovascular diseases, cancers, and central nervous system diseases, etc. Cardiovascular disease is still named as the number one cause of death globally, with myocardial ischemia (MI) accounting for 15 % of mortality annually. A number of circRNAs have been identified and are being studied for their ability to reduce MI by inhibiting the molecular mechanisms associated with myocardial ischemia reperfusion injury, such as inflammation, oxidative stress, autophagy, apoptosis, and so on. CircRNAs play a significant role as crucial regulatory elements at transcriptional levels, regulating different proteins, and at posttranscriptional levels, having interactions with RNA-binding proteins, ribosomal proteins, micro-RNAS, and long non-coding RNAS, making it possible to exert their effects through the circRNA-miRNA-mRNA axis. CircRNAs are a potential novel biomarker and therapeutic target for myocardial ischemia and cardiovascular diseases in general. The purpose of this review is to summarize the relationship, function, and mechanism observed between circRNAs and MI injury, as well as to provide directions for future research and clinical trials.
Sujet(s)
Ischémie myocardique , ARN circulaire , ARN circulaire/génétique , ARN circulaire/métabolisme , Humains , Ischémie myocardique/génétique , Ischémie myocardique/métabolisme , Animaux , Marqueurs biologiques/métabolisme , microARN/génétique , Stress oxydatifRÉSUMÉ
Despite recent progress, ischemic heart disease poses a persistent global challenge, driving significant morbidity and mortality. The pursuit of therapeutic solutions has led to the emergence of strategies such as ischemic preconditioning, postconditioning, and remote conditioning to shield the heart from myocardial ischemia/reperfusion injury (MIRI). These ischemic conditioning approaches, applied before, after, or at a distance from the affected organ, inspire future therapeutic strategies, including pharmacological conditioning. Gasotransmitters, comprising nitric oxide, hydrogen sulfide, sulfur dioxide, and carbon monoxide, play pivotal roles in physiological and pathological processes, exhibiting shared features such as smooth muscle relaxation, antiapoptotic effects, and anti-inflammatory properties. Despite potential risks at high concentrations, physiological levels of gasotransmitters induce vasorelaxation and promote cardioprotective effects. Noble gases, notably argon, helium, and xenon, exhibit organ-protective properties by reducing cell death, minimizing infarct size, and enhancing functional recovery in post-ischemic organs. The protective role of noble gases appears to hinge on their modulation of molecular pathways governing cell survival, leading to both pro- and antiapoptotic effects. Among noble gases, helium and xenon emerge as particularly promising in the field of cardioprotection. This overview synthesizes our current understanding of the roles played by gasotransmitters and noble gases in the context of MIRI and cardioprotection. In addition, we underscore potential future developments involving the utilization of noble gases and gasotransmitter donor molecules in advancing cardioprotective strategies.
Sujet(s)
Gazotransmetteurs , Lésion de reperfusion myocardique , Gaz rares , Humains , Gazotransmetteurs/métabolisme , Gazotransmetteurs/usage thérapeutique , Animaux , Lésion de reperfusion myocardique/prévention et contrôle , Lésion de reperfusion myocardique/métabolisme , Lésion de reperfusion myocardique/anatomopathologie , Lésion de reperfusion myocardique/physiopathologie , Gaz rares/métabolisme , Préconditionnement ischémique myocardique , Transduction du signal , Cardiotoniques/pharmacologie , Cardiotoniques/usage thérapeutique , Ischémie myocardique/métabolisme , Ischémie myocardique/physiopathologieRÉSUMÉ
Myocardial ischemia is the leading cause of health loss from cardiovascular disease worldwide. Myocardial ischemia and hypoxia during exercise trigger the risk of sudden exercise death which, in severe cases, will further lead to myocardial infarction. The Nrf2 transcription factor is an important antioxidant regulator that is extensively engaged in biological processes such as oxidative stress, inflammatory response, apoptosis, and mitochondrial malfunction. It has a significant role in the prevention and treatment of several cardiovascular illnesses, since it can control not only the expression of several antioxidant genes, but also the target genes of associated pathological processes. Therefore, targeting Nrf2 will have great potential in the treatment of myocardial ischemic injury. Natural products are widely used to treat myocardial ischemic diseases because of their few side effects. A large number of studies have shown that the Nrf2 transcription factor can be used as an important way for natural products to alleviate myocardial ischemia. However, the specific role and related mechanism of Nrf2 in mediating natural products in the treatment of myocardial ischemia is still unclear. Therefore, this review combs the key role and possible mechanism of Nrf2 in myocardial ischemic injury, and emphatically summarizes the significant role of natural products in treating myocardial ischemic symptoms, thus providing a broad foundation for clinical transformation.
Sujet(s)
Produits biologiques , Ischémie myocardique , Facteur-2 apparenté à NF-E2 , Transduction du signal , Facteur-2 apparenté à NF-E2/métabolisme , Humains , Produits biologiques/pharmacologie , Produits biologiques/usage thérapeutique , Produits biologiques/composition chimique , Transduction du signal/effets des médicaments et des substances chimiques , Ischémie myocardique/métabolisme , Ischémie myocardique/traitement médicamenteux , Ischémie myocardique/anatomopathologie , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Antioxydants/usage thérapeutiqueRÉSUMÉ
Ischemic heart diseases and cardiomyopathies are characterized by hypoxia, energy starvation and mitochondrial dysfunction. HIF-1 acts as a cellular oxygen sensor, tuning the balance of metabolic and oxidative stress pathways to provide ATP and sustain cell survival. Acting on mitochondria, HIF-1 regulates different processes such as energy substrate utilization, oxidative phosphorylation and mitochondrial dynamics. In turn, mitochondrial homeostasis modifications impact HIF-1 activity. This underlies that HIF-1 and mitochondria are tightly interconnected to maintain cell homeostasis. Despite many evidences linking HIF-1 and mitochondria, the mechanistic insights are far from being understood, particularly in the context of cardiac diseases. Here, we explore the current understanding of how HIF-1, reactive oxygen species and cell metabolism are interconnected, with a specific focus on mitochondrial function and dynamics. We also discuss the divergent roles of HIF in acute and chronic cardiac diseases in order to highlight that HIF-1, mitochondria and oxidative stress interaction deserves to be deeply investigated. While the strategies aiming at stabilizing HIF-1 have provided beneficial effects in acute ischemic injury, some deleterious effects were observed during prolonged HIF-1 activation. Thus, deciphering the link between HIF-1 and mitochondria will help to optimize HIF-1 modulation and provide new therapeutic perspectives for the treatment of cardiovascular pathologies.
Sujet(s)
Cardiopathies , Stress oxydatif , Espèces réactives de l'oxygène , Humains , Cardiopathies/métabolisme , Cardiopathies/anatomopathologie , Cardiopathies/génétique , Animaux , Espèces réactives de l'oxygène/métabolisme , Facteur-1 induit par l'hypoxie/métabolisme , Facteur-1 induit par l'hypoxie/génétique , Mitochondries du myocarde/métabolisme , Mitochondries du myocarde/anatomopathologie , Mitochondries/métabolisme , Mitochondries/anatomopathologie , Mitochondries/génétique , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Phosphorylation oxydative , Ischémie myocardique/métabolisme , Ischémie myocardique/anatomopathologie , Ischémie myocardique/génétiqueRÉSUMÉ
Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.