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Circulation Research May 2021Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover... (Review)
Review
Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.
Topics: Adaptive Immunity; B-Lymphocytes; Bioengineering; Cytokines; Disease Progression; Eosinophils; Fibroblasts; Fibrosis; Heart Failure; Heart Injuries; Humans; Immunotherapy; Immunotherapy, Adoptive; Macrophages; Mast Cells; Monocytes; Myocardium; Myocytes, Cardiac; Neutrophils; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 34043424
DOI: 10.1161/CIRCRESAHA.121.318005 -
Military Medical Research Apr 2023Heart injury such as myocardial infarction leads to cardiomyocyte loss, fibrotic tissue deposition, and scar formation. These changes reduce cardiac contractility,... (Review)
Review
Heart injury such as myocardial infarction leads to cardiomyocyte loss, fibrotic tissue deposition, and scar formation. These changes reduce cardiac contractility, resulting in heart failure, which causes a huge public health burden. Military personnel, compared with civilians, is exposed to more stress, a risk factor for heart diseases, making cardiovascular health management and treatment innovation an important topic for military medicine. So far, medical intervention can slow down cardiovascular disease progression, but not yet induce heart regeneration. In the past decades, studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury. Insights have emerged from studies in animal models and early clinical trials. Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease. In this review, we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.
Topics: Animals; Cicatrix; Regeneration; Myocytes, Cardiac; Myocardial Infarction; Heart Diseases; Heart Injuries
PubMed: 37098604
DOI: 10.1186/s40779-023-00452-0 -
Molecular Medicine Reports Jul 2020Cardiac dysfunction resulting from sepsis may cause significant morbidity and mortality, and ferroptosis plays a role in this pathology. Dexmedetomidine (Dex), a...
Cardiac dysfunction resulting from sepsis may cause significant morbidity and mortality, and ferroptosis plays a role in this pathology. Dexmedetomidine (Dex), a α2‑adrenergic receptor (α2‑AR) agonist exerts cardioprotective effects against septic heart dysfunction, but the exact mechanism is unknown. In the present study, sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Dex and yohimbine hydrochloride (YOH), an α2‑AR inhibitor, were administered before inducing CLP. Then, 24 h after CLP, serum and heart tissue were collected to detect changes of troponin‑I (TN‑I), interleukin 6 (IL‑6), superoxide dismutase (SOD), malonaldehyde (MDA) and glutathione (GSH) levels, and iron release. Ferroptosis‑targeting proteins, apoptosis and inflammatory factors were assessed by western blotting or ELISA. It was found that, 24 h after CLP, TN‑I, a biomarker of myocardial injury, was significantly increased compared with the control group. Furthermore, the levels of MDA, 8‑hydroxy‑2'‑deoxyguanosine and the inflammatory factors IL‑6 and monocyte chemoattractant protein‑1 were also significantly increased. It was demonstrated that treatment with Dex reverted or attenuated these changes (CLP + Dex vs. CLP; P<0.05), but these protective effects of Dex were reversed by YOH. Moreover, CLP significantly decreased the protein expression levels of glutathione peroxidase 4 (GPX4), SOD and GSH. However, CLP increased expression levels of heme oxygenase‑1 (HO‑1), transferrin receptor, cleaved caspase 3, inducible nitric oxide synthase and gasdermin D, and iron concentrations. It was found that Dex reversed these changes, but YOH abrogated the protective effects of Dex (CLP + Dex + YOH vs. CLP + Dex; P<0.05). Therefore, the present results suggested that the attenuation of sepsis‑induced HO‑1 overexpression and iron concentration, and the reduction of ferroptosis via enhancing GPX4, may be the major mechanisms via which Dex alleviates sepsis‑induced myocardial cellular injury.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Dexmedetomidine; Ferroptosis; Heart; Heart Injuries; Male; Mice, Inbred C57BL; Myocardium; Sepsis
PubMed: 32377745
DOI: 10.3892/mmr.2020.11114 -
Journal of Extracellular Vesicles Feb 2021Extracellular vesicles (EVs) curb important biological functions. We previously disclosed that ischemia-reperfusion (IR) induces increased release of EVs (IR-EVs) in the...
Extracellular vesicles (EVs) curb important biological functions. We previously disclosed that ischemia-reperfusion (IR) induces increased release of EVs (IR-EVs) in the heart. However, the role of IR-EVs in IR pathological process remains poorly understood. Here we found that adoptive transfer of IR-EVs aggravated IR induced heart injury, and EV inhibition by GW4869 reduced the IR injury. Our in vivo and in vitro investigations substantiated that IR-EVs facilitated M1-like polarization of macrophages with increased expression of proinflammatory cytokines. Further, we disclosed the miRNA profile in cardiac EVs and confirmed the enrichment of miRNAs, such as miR-155-5p in IR-EVs compared to EVs from the sham heart (S-EVs). In particular, IR-EVs transferred miR-155-5p to macrophages and enhanced the inflammatory response through activating JAK2/STAT1 pathway. Interestingly, IR-EVs not only boosted the local inflammation in the heart, but even triggered systemic inflammation in distant organs. Taken together, we newly identify an IR-EVs-miR-155-5pM1 polarization axis in the heart post IR. The EVs derived from IR-injured heart contribute to both local and systemic inflammation. Importantly, EV inhibition by GW4869 is supposed to be a promising therapeutic strategy for IR injury.
Topics: Aniline Compounds; Animals; Benzylidene Compounds; Cytokines; Disease Models, Animal; Extracellular Vesicles; Heart Injuries; Inflammation; Janus Kinase 2; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Microscopy, Confocal; Myocardial Ischemia; Myocardial Reperfusion Injury; STAT1 Transcription Factor; Signal Transduction
PubMed: 33664937
DOI: 10.1002/jev2.12072 -
Cells Apr 2022Ischemic heart disease is a leading cause of morbidity and mortality worldwide [...].
Ischemic heart disease is a leading cause of morbidity and mortality worldwide [...].
Topics: Heart Injuries; Humans; Ischemia; Morbidity; Myocardial Ischemia
PubMed: 35563690
DOI: 10.3390/cells11091384 -
Current Topics in Developmental Biology 2012The heart is a pump that is comprised of cardiac myocytes and other cell types and whose proper function is critical to quality of life. The ability to trigger... (Review)
Review
The heart is a pump that is comprised of cardiac myocytes and other cell types and whose proper function is critical to quality of life. The ability to trigger regeneration of heart muscle following injury eludes adult mammals, a deficiency of great clinical impact. Major research efforts are attempting to change this through advances in cell therapy or activating endogenous regenerative mechanisms that exist only early in life. In contrast with mammals, lower vertebrates like zebrafish demonstrate an impressive natural capacity for cardiac regeneration throughout life. This review will cover recent progress in the field of heart regeneration with a focus on endogenous regenerative capacity and its potential manipulation.
Topics: Animals; Cell- and Tissue-Based Therapy; Disease Models, Animal; Heart; Heart Injuries; Humans; Regeneration
PubMed: 22449849
DOI: 10.1016/B978-0-12-387786-4.00010-5 -
Redox Biology May 2018Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose...
Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor recently approved for treatment of type 2 diabetes, promotes glycosuria excretion and offers cardioprotective actions beyond its glucose-lowering effects. This study was designed to evaluate the effect of empagliflozin on cardiac microvascular injury in diabetes and the underlying mechanism involved with a focus on mitochondria. Our data revealed that empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion. Further study suggested that empagliflozin exerted its effects through inhibition of mitochondrial fission in an adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Empagliflozin restored AMP-to-ATP ratio to trigger AMPK activation, suppressed Drp1 phosphorylation, and increased Drp1 phosphorylation, ultimately leading to inhibition of mitochondrial fission. The empagliflozin-induced inhibition of mitochondrial fission preserved cardiac microvascular endothelial cell (CMEC) barrier function through suppressed mitochondrial reactive oxygen species (mtROS) production and subsequently oxidative stress to impede CMEC senescence. Empagliflozin-induced fission loss also favored angiogenesis by promoting CMEC migration through amelioration of F-actin depolymerization. Taken together, these results indicated the therapeutic promises of empagliflozin in the treatment of pathological microvascular changes in diabetes.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Endothelial Cells; Glucosides; Heart Injuries; Humans; Mice; Mitochondria; Mitochondrial Dynamics; Protein Kinases
PubMed: 29306791
DOI: 10.1016/j.redox.2017.12.019 -
World Journal of Emergency Surgery :... May 2023The diagnosis of cardiac contusion, caused by blunt chest trauma, remains a challenge due to the non-specific symptoms it causes and the lack of ideal tests to diagnose... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The diagnosis of cardiac contusion, caused by blunt chest trauma, remains a challenge due to the non-specific symptoms it causes and the lack of ideal tests to diagnose myocardial damage. A cardiac contusion can be life-threatening if not diagnosed and treated promptly. Several diagnostic tests have been used to evaluate the risk of cardiac complications, but the challenge of identifying patients with contusions nevertheless remains.
AIM OF THE STUDY
To evaluate the accuracy of diagnostic tests for detecting blunt cardiac injury (BCI) and its complications, in patients with severe chest injuries, who are assessed in an emergency department or by any front-line emergency physician.
METHODS
A targeted search strategy was performed using Ovid MEDLINE and Embase databases from 1993 up to October 2022. Data on at least one of the following diagnostic tests: electrocardiogram (ECG), serum creatinine phosphokinase-MB level (CPK-MB), echocardiography (Echo), Cardiac troponin I (cTnI) or Cardiac troponin T (cTnT). Diagnostic tests for cardiac contusion were evaluated for their accuracy in meta-analysis. Heterogeneity was assessed using the I and the QUADAS-2 tool was used to assess bias of the studies.
RESULTS
This systematic review yielded 51 studies (n = 5,359). The weighted mean incidence of myocardial injuries after sustaining a blunt force trauma stood at 18.3% of cases. Overall weighted mean mortality among patients with blunt cardiac injury was 7.6% (1.4-36.4%). Initial ECG, cTnI, cTnT and transthoracic echocardiography TTE all showed high specificity (> 80%), but lower sensitivity (< 70%). TEE had a specificity of 72.1% (range 35.8-98.2%) and sensitivity of 86.7% (range 40-99.2%) in diagnosing cardiac contusion. CK-MB had the lowest diagnostic odds ratio of 3.598 (95% CI: 1.832-7.068). Normal ECG accompanied by normal cTnI showed a high sensitivity of 85% in ruling out cardiac injuries.
CONCLUSION
Emergency physicians face great challenges in diagnosing cardiac injuries in patients following blunt trauma. In the majority of cases, joint use of ECG and cTnI was a pragmatic and cost-effective approach to rule out cardiac injuries. In addition, TEE may be highly accurate in identifying cardiac injuries in suspected cases.
Topics: Humans; Thoracic Injuries; Wounds, Nonpenetrating; Heart Injuries; Myocardial Contusions; Troponin I; Troponin T; Diagnostic Tests, Routine
PubMed: 37245048
DOI: 10.1186/s13017-023-00504-9 -
Redox Biology May 2018Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its...
Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity.
Topics: Animals; Cardiotoxicity; Cell Line; Cell Survival; Doxorubicin; Gene Expression Regulation; Heart Injuries; Humans; MicroRNAs; Myocardium; Myocytes, Cardiac; NF-E2-Related Factor 2; Neoplasms; Oxidative Stress; Rats; Sirtuin 2
PubMed: 29304479
DOI: 10.1016/j.redox.2017.12.013 -
Annals of the New York Academy of... Jun 2016Chlorine (Cl2 ) is utilized worldwide for a diverse range of industrial applications, including pulp bleaching, sanitation, and pharmaceutical development. Though Cl2... (Review)
Review
Chlorine (Cl2 ) is utilized worldwide for a diverse range of industrial applications, including pulp bleaching, sanitation, and pharmaceutical development. Though Cl2 has widespread use, little is known regarding the mechanisms of toxicity associated with Cl2 exposure, which occurs during industrial accidents or acts of terrorism. Previous instances of Cl2 exposure have led to reported episodes of respiratory distress that result in high morbidity and mortality. Furthermore, studies suggest that acute Cl2 exposure also results in systemic vascular injury and subsequent myocardial contractile dysfunction. Here, we review both lung and cardiac pathology associated with acute Cl2 inhalation and discuss recently published data that suggest that mitochondrial dysfunction underlies the pathogenesis of Cl2 -induced toxicity. Last, we discuss our findings that suggest that upregulation of autophagy protects against Cl2 -induced lung inflammation and can be a potential therapeutic target for ameliorating the toxic effects of Cl2 exposure.
Topics: Animals; Chlorine; Environmental Exposure; Heart Injuries; Humans; Lung Injury; Mitochondria; Public Health
PubMed: 27303906
DOI: 10.1111/nyas.13091