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Trends in Cardiovascular Medicine Aug 2023Acute myocardial infarction is caused by a sudden coronary artery occlusion and leads to ischemia in the corresponding myocardial territory which generally results in... (Review)
Review
Acute myocardial infarction is caused by a sudden coronary artery occlusion and leads to ischemia in the corresponding myocardial territory which generally results in myocardial necrosis. Without restoration of coronary perfusion, myocardial scar formation will cause adverse remodelling of the myocardium and heart failure. Successful introduction of percutaneous coronary intervention and surgical coronary artery bypass grafting made it possible to achieve early revascularisation/reperfusion, hence limiting the ischemic zone of myocardium. However, reperfusion by itself paradoxically triggers an exacerbated and accelerated injury in the myocardium, called ischemia-reperfusion (I/R) injury. This mechanism is partially driven by inflammation through multiple interacting pathways. In this review we summarize the current insights in mechanisms of I/R injury and the influence of altered inflammation. Multiple pharmacological and interventional therapeutic strategies (ischemic conditioning) have proven to be beneficial during I/R in preclinical models but were notoriously unsuccessful upon clinical translation. In this review we focus on common mechanisms of I/R injury, altered inflammation and potential therapeutic strategies. We hypothesize that a dual approach may be of value because I/R injury patients are predestined with multiple comorbidities and systemic low-grade inflammation, which requires targeted intervention before other strategies can be fully effective.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Infarction; Myocardium; Heart; Inflammation; Myocardial Ischemia
PubMed: 35181472
DOI: 10.1016/j.tcm.2022.02.005 -
Microvascular Research Sep 2023Cardiovascular diseases are one of the leading causes of mortality in developed countries. Among cardiovascular disorders, myocardial infarction remains a... (Review)
Review
Cardiovascular diseases are one of the leading causes of mortality in developed countries. Among cardiovascular disorders, myocardial infarction remains a life-threatening problem predisposing to the development and progression of ischemic heart failure. Ischemia/reperfusion (I/R) injury is a critical cause of myocardial injury. In recent decades, many efforts have been made to find the molecular and cellular mechanisms underlying the development of myocardial I/R injury and post-ischemic remodeling. Some of these mechanisms are mitochondrial dysfunction, metabolic alterations, inflammation, high production of ROS, and autophagy deregulation. Despite continuous efforts, myocardial I/R injury remains a major challenge in medical treatments of thrombolytic therapy, heart disease, primary percutaneous coronary intervention, and coronary arterial bypass grafting. The development of effective therapeutic strategies to reduce or prevent myocardial I/R injury is of great clinical significance.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Infarction; Heart Failure
PubMed: 37307911
DOI: 10.1016/j.mvr.2023.104565 -
Trends in Endocrinology and Metabolism:... Mar 2024Myocardial ischemia-reperfusion (I/R) injury most commonly occurs in coronary artery disease when prompt reperfusion is used to salvage the ischemic myocardium.... (Review)
Review
Myocardial ischemia-reperfusion (I/R) injury most commonly occurs in coronary artery disease when prompt reperfusion is used to salvage the ischemic myocardium. Cardiomyocyte death is a significant component of myocardial I/R injury and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of cell death, ferroptosis, necroptosis, and pyroptosis have been shown to be involved in myocardial I/R. These new forms of regulated cell death cause cardiomyocyte loss and exacerbate I/R injury by affecting reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, subsequently mediating adverse remodeling, cardiac dysfunction, and heart failure. Herein, we review the roles of ferroptosis, necroptosis, and pyroptosis in myocardial I/R and discuss their contribution to pathology.
Topics: Humans; Myocardial Reperfusion Injury; Apoptosis; Myocytes, Cardiac; Myocardial Ischemia; Pyroptosis; Coronary Artery Disease
PubMed: 37981501
DOI: 10.1016/j.tem.2023.10.010 -
Biomedicine & Pharmacotherapy =... Jul 2023Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways... (Review)
Review
Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways and signaling pathways. Among these pathways, glucose metabolism and lipid metabolism play important roles in regulating myocardial energy metabolism. Therefore, this article focuses on the roles of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion injury, including glycolysis, glucose uptake and transport, glycogen metabolism and the pentose phosphate pathway; and triglyceride metabolism, fatty acid uptake and transport, phospholipid metabolism, lipoprotein metabolism, and cholesterol metabolism. Finally, due to the different alterations and development of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion, there are also complex interregulatory relationships between them. In the future, modulating the equilibrium between glucose metabolism and lipid metabolism in cardiomyocytes and ameliorating aberrations in myocardial energy metabolism represent highly promising novel strategies for addressing myocardial ischemia-reperfusion injury. Therefore, a comprehensive exploration of glycolipid metabolism can offer novel theoretical and clinical insights into the prevention and treatment of myocardial ischemia-reperfusion injury.
Topics: Humans; Myocardial Reperfusion Injury; Glucose; Lipid Metabolism; Myocardial Ischemia; Myocardium
PubMed: 37141734
DOI: 10.1016/j.biopha.2023.114827 -
Circulation Research Aug 2023Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing...
BACKGROUND
Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT.
METHODS
Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 []-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq (RNA sequencing) was performed in BAT from WT and mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b.
RESULTS
Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, -deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to -deficient mice reduced I/R injury whereas transplanting BAT from -deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury.
CONCLUSIONS
The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.
Topics: Animals; Humans; Mice; Adipose Tissue, Brown; Coronary Artery Disease; Growth Differentiation Factor 10; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Reperfusion
PubMed: 37462036
DOI: 10.1161/CIRCRESAHA.122.322337 -
EBioMedicine Sep 2023Macrophage infiltration and polarization are integral to the progression of heart failure and cardiac fibrosis after ischemia/reperfusion (IR). Interleukin 34 (IL-34) is...
BACKGROUND
Macrophage infiltration and polarization are integral to the progression of heart failure and cardiac fibrosis after ischemia/reperfusion (IR). Interleukin 34 (IL-34) is an inflammatory regulator related to a series of autoimmune diseases. Whether IL-34 mediates inflammatory responses and contributes to cardiac remodeling and heart failure post-IR remains unclear.
METHODS
IL-34 knock-out mice were used to determine the role of IL-34 on cardiac remodeling after IR surgery. Then, immunofluorescence, flow cytometry assays, and RNA-seq analysis were performed to explore the underlying mechanisms of IL-34-induced macrophage recruitment and polarization, and further heart failure after IR.
FINDINGS
By re-analyzing single-cell RNA-seq and single-nucleus RNA-seq data of murine and human ischemic hearts, we showed that IL-34 expression was upregulated after IR. IL-34 knockout mitigated cardiac remodeling, cardiac dysfunction, and fibrosis after IR and vice versa. RNA-seq analysis revealed that IL-34 deletion correlated negatively with immune responses and chemotaxis after IR injury. Consistently, immunofluorescence and flow cytometry assays demonstrated that IL-34 deletion attenuated macrophage recruitment and CCR2+ macrophage polarization. Mechanistically, IL-34 deficiency repressed both the canonical and noncanonical NF-κB signaling pathway, leading to marked reduction of P-IKKβ and P-IκBα kinase levels; downregulation of NF-κB p65, RelB, and p52 expression, which drove the decline in chemokine CCL2 expression. Finally, IL-34 and CCL2 levels were increased in the serum of acute coronary syndrome patients, with a positive correlation between circulating IL-34 and CCL2 levels in clinical patients.
INTERPRETATION
In conclusion, IL-34 sustains NF-κB pathway activation to elicit increased CCL2 expression, which contributes to macrophage recruitment and polarization, and subsequently exacerbates cardiac remodeling and heart failure post-IR. Strategies targeting IL-34-centered immunomodulation may provide new therapeutic approaches to prevent and reverse cardiac remodeling and heart failure in clinical MI patients after percutaneous coronary intervention.
FUNDING
This study was supported by the National Nature Science Foundation of China (81670352 and 81970327 to R T, 82000368 to Q F).
Topics: Animals; Humans; Mice; Heart Failure; I-kappa B Kinase; Interleukins; Macrophages; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Signal Transduction; Ventricular Remodeling
PubMed: 37556943
DOI: 10.1016/j.ebiom.2023.104744 -
International Immunopharmacology Oct 2023Myocardial ischemia has a high incidence and mortality rate, and reperfusion is currently the standard intervention. However, reperfusion may lead to further myocardial... (Review)
Review
Myocardial ischemia has a high incidence and mortality rate, and reperfusion is currently the standard intervention. However, reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MIRI). There are currently no effective clinical treatments for MIRI. The PI3K/Akt signaling pathway is involved in cardiovascular health and disease and plays an important role in reducing myocardial infarct size and restoring cardiac function after MIRI. Activation of the PI3K/Akt pathway provides myocardial protection through synergistic upregulation of antioxidant, anti-inflammatory, and autophagy activities and inhibition of mitochondrial dysfunction and cardiomyocyte apoptosis. Many studies have shown that PI3K/Akt has a significant protective effect against MIRI. Here, we reviewed the molecular regulation of PI3K/Akt in MIRI and summarized the molecular mechanism by which PI3K/Akt affects MIRI, the effects of ischemic preconditioning and ischemic postconditioning, and the role of related drugs or activators targeting PI3K/Akt in MIRI, providing novel insights for the formulation of myocardial protection strategies. This review provides evidence of the role of PI3K/Akt activation in MIRI and supports its use as a therapeutic target.
Topics: Humans; Proto-Oncogene Proteins c-akt; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Signal Transduction; Myocardial Ischemia; Apoptosis
PubMed: 37523969
DOI: 10.1016/j.intimp.2023.110714 -
Angewandte Chemie (International Ed. in... Sep 2023Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Medications or surgery have been considered as effective protocols to treat IHD for...
Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Medications or surgery have been considered as effective protocols to treat IHD for decades. Yet the reperfusion of the blood flow frequently leads to the generation of excessive reactive oxygen species (ROS), causing prominent and irreversible damage to the cardiomyocytes. In the present work, tannic acid-assembled tetravalent cerium (TA-Ce) nanocatalysts with appealing cardiomyocyte-targeting and antioxidation capability have been synthesized and applied for the effective and biocompatible ischemia/reperfusion injury therapeutics. TA-Ce nanocatalysts could effectively rescue the cardiomyocytes from oxidative stress induced by H O challenge as well as oxygen-glucose deprivation in vitro. In the murine ischemia/reperfusion model, cardiac accumulation and intracellular ROS scavenging could be achieved against the pathology, substantially reducing the myocardial infarct area and recovering heart functionality. This work illuminates the design of nanocatalytic metal complexes and their therapeutic prospects in ischemic heart diseases with high effectiveness and biocompatibility, paving the way for the clinical translation from bench to bedside.
Topics: Mice; Animals; Reactive Oxygen Species; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Myocardial Infarction; Oxidative Stress
PubMed: 37368480
DOI: 10.1002/anie.202305576 -
Pharmacological Research Jan 2024SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase. It is involved in the regulation of various pathophysiological... (Review)
Review
SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase. It is involved in the regulation of various pathophysiological processes, including cell proliferation, survival, differentiation, autophagy, and oxidative stress. Therapeutic activation of SIRT1 protects the heart and cardiomyocytes from pathology-related stress, particularly myocardial ischemia/reperfusion (I/R). Autophagy is an important metabolic pathway for cell survival during energy or nutrient deficiency, hypoxia, or oxidative stress. Autophagy is a double-edged sword in myocardial I/R injury. The activation of autophagy during the ischemic phase removes excess metabolic waste and helps ensure cardiomyocyte survival, whereas excessive autophagy during reperfusion depletes the cellular components and leads to autophagic cell death. Increasing research on I/R injury has indicated that SIRT1 is involved in the process of autophagy and regulates myocardial I/R. SIRT1 regulates autophagy through various pathways, such as the deacetylation of FOXOs, ATGs, and LC3. Recent studies have confirmed that SIRT1-mediated autophagy plays different roles at different stages of myocardial I/R injury. By targeting the mechanism of SIRT1-mediated autophagy at different stages of I/R injury, new small-molecule drugs, miRNA activators, or blockers can be developed. For example, resveratrol, sevoflurane, quercetin, and melatonin in the ischemic stage, coptisine, curcumin, berberine, and some miRNAs during reperfusion, were involved in regulating the SIRT1-autophagy axis, exerting a cardioprotective effect. Here, we summarize the possible mechanisms of autophagy regulation by SIRT1 in myocardial I/R injury and the related molecular drug applications to identify strategies for treating myocardial I/R injury.
Topics: Humans; Myocardial Reperfusion Injury; Sirtuin 1; Myocardial Ischemia; Myocytes, Cardiac; Coronary Artery Disease; Reperfusion; Autophagy; Apoptosis
PubMed: 37820856
DOI: 10.1016/j.phrs.2023.106957 -
Food & Function Nov 2023: Myocardial ischemia and reperfusion injury (MIRI) is a severe complication of revascularization therapy in patients with myocardial infarction. Therefore, there is an...
: Myocardial ischemia and reperfusion injury (MIRI) is a severe complication of revascularization therapy in patients with myocardial infarction. Therefore, there is an urgent requirement to find more therapeutic solutions for MIRI. Recently, ferroptosis, which is characterized by lipid peroxidation, was considered a critical contributor to MIRI. Fucoxanthin (FX), a natural antioxidant carotenoid, which is abundant in brown seaweed, exerts protective effects under various pathological conditions. However, whether FX alleviates MIRI is unclear. This study aims to clarify the effects of FX on MIRI. : Mice with left anterior descending artery ligation and reperfusion were used as models. Neonatal rat cardiomyocytes (NRCs) induced with hypoxia and reperfusion were used as models. TTC-Evans blue staining was performed to validate the infarction size. Transmission electron microscopy was employed to detect mitochondrial injury in cardiomyocytes. In addition, 4 weeks after MIRI, echocardiography was performed to measure cardiac function; fluorescent probes and western blots were used to detect ferroptosis. : TTC-Evans blue staining showed that FX reduced the infarction size induced by MIRI. Transmission electron microscopy showed that FX ameliorated the MIRI-induced myofibril loss and mitochondrion shrinkage. Furthermore, FX improved LVEF and LVFS and inhibited myocardial hypertrophy and fibrosis after 4 weeks in mice with MIRI. In the study, calcein AM/PI staining and TUNEL staining showed that FX reduced cell death caused by hypoxia and reperfusion treatment. DCFH-DA and MitoSOX probes indicated that FX inhibited cellular and mitochondrial reactive oxygen species (ROS). Moreover, C11-BODIPY 581/591 staining, ferro-orange staining, MDA assay, Fe assay, 4-hydroxynonenal enzyme-linked immunosorbent assay, and western blot were performed and the results revealed that FX ameliorated ferroptosis and , as indicated by inhibiting lipid ROS and Fe release, as well as by modulating ferroptosis hallmark FTH, TFRC, and GPX4 expression. Additionally, the protective effects of FX were eliminated by the NRF2 inhibitor brusatol, as observed from western blotting, C11-BODIPY 581/591 staining, and calcein AM/PI staining, indicating that FX exerted cardio-protective effects on MIRI through the NRF2 pathway. : Our study showed that FX alleviated MIRI through the inhibition of ferroptosis the NRF2 signaling pathway.
Topics: Humans; Rats; Mice; Animals; NF-E2-Related Factor 2; Ferroptosis; Reactive Oxygen Species; Evans Blue; Rats, Sprague-Dawley; Signal Transduction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial Infarction; Coronary Artery Disease; Hypoxia
PubMed: 37861458
DOI: 10.1039/d3fo02633g