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Platelets Protect Cardiomyocytes from Ischaemic Damage.

ABSTRACT: Platelets are classically known for their roles in bleeding control and occlusive thrombus formation causing ischaemic tissue damage. Recently non-classical roles for platelets have been described, many of which may be mediated by the heterogeneous cargo that platelets secrete from granular stores upon activation. Using an in vitro model of ischaemic injury to ventricular cardiomyocytes, we observed that platelets, through secreted factors, delayed the rate of cardiomyocyte death during ischaemia. This protective effect appeared independent of platelet dense granule cargo, but required α-granule components stromal cell-derived factor (SDF)-1α and transforming growth factor (TGF) β1. Protein kinase C (PKC) activity within cardiomyocytes was responsible for mediating the protective signals initiated by the released platelet cargo. Importantly, pretreating platelets with a P2Y₁₂ antagonist, but not the cyclooxygenase inhibitor aspirin, substantially attenuated this protective effect. These findings therefore reveal a paradoxically protective role for platelet activation during cardiac ischaemia and could have important implications for the use of anti-platelet therapeutics in the management of myocardial infarction.

SUBMITTER: Walsh TG

PROVIDER: S-EPMC6241850 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitochondrial-Derived Vesicles Protect Cardiomyocytes Against Hypoxic Damage.

Project description:Myocardial ischemia is a condition with insufficient oxygen supporting the heart tissues, which may result from myocardial infarction or trauma-induced hemorrhagic shock. In order to develop better preventive and therapeutic strategies for myocardial ischemic damage, it is important that we understand the mechanisms underlying this type of injury. Mitochondrial-derived vesicles (MDVs) have been proposed as a novel player in maintaining mitochondrial quality control. This study aimed to investigate the role and possible mechanisms of MDVs in ischemia/hypoxia-induced myocardial apoptosis. H9C2 cardiomyocytes were used for the cellular experiments. A 40% fixed blood volume hemorrhagic shock rat model was used to construct the acute general ischemic models. MDVs were detected using immunofluorescence staining with PDH and TOM20. Exogenous MDVs were reconstituted in vitro from isolated mitochondria under different hypoxic conditions. The results demonstrate that MDV production was negatively correlated with cardiomyocyte apoptosis under hypoxic conditions; exogenous MDVs inhibited hypoxia-induced cardiomyocyte apoptosis; and MDV-mediated protection against hypoxia-induced cardiomyocyte apoptosis was accomplished via Bcl-2 interactions in the mitochondrial pathway. This study provides evidence that MDVs protect cardiomyocytes against hypoxic damage by inhibiting mitochondrial apoptosis. Our study used a novel approach that expands our understanding of MDVs and highlights that MDVs may be part of the endogenous response to hypoxia designed to mitigate damage. Strategies that stimulate cardiomyocytes to produce cargo-specific MDVs, including Bcl-2 containing MDVs, could theoretically be helpful in treating ischemic/hypoxic myocardial injury.

| S-EPMC7212461 | biostudies-literature

Mesenchymal stromal cells protect human cardiomyocytes from amyloid fibril damage.

Project description:Background aimsLight chain (AL) amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. Patients with LC amyloid involvement of the heart have the worst morbidity and mortality. Current treatments target the plasma cells to reduce further production of amyloid proteins. There is dire need to understand the mechanisms of cardiac tissue damage from amyloid to develop novel therapies. We recently reported that LC soluble and fibrillar species cause apoptosis and inhibit cell growth in human cardiomyocytes. Mesenchymal stromal cells (MSCs) can promote wound healing and tissue remodeling. The objective of this study was to evaluate MSCs to protect cardiomyocytes affected by AL amyloid fibrils.MethodsWe used live cell imaging and proteomics to analyze the effect of MSCs in the growth arrest caused by AL amyloid fibrils.ResultsWe evaluated the growth of human cardiomyocytes (RFP-AC16 cells) in the presence of cytotoxic LC amyloid fibrils. MSCs reversed the cell growth arrest caused by LC fibrils. We also demonstrated that this effect requires cell contact and may be mediated through paracrine factors modulating cell adhesion and extracellular matrix remodeling. To our knowledge, this is the first report of MSC protection of human cardiomyocytes in amyloid disease.ConclusionsThis important proof of concept study will inform future rational development of MSC therapy in cardiac LC amyloid.

| S-EPMC6456258 | biostudies-literature

Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes.

Project description:Cardiovascular diseases (CVDs) are the most common non-communicable diseases globally. An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Mitochondria play critical roles in cellular metabolic homeostasis, cell survival, and cell death, as well as producing most of the cell's energy. Protein-protein interactions (PPIs) have a significant role in physiological and pathological processes, and aberrant PPIs are associated with various diseases, therefore they are potential drug targets for a broad range of therapeutic areas. Due to their ability to mimic natural interaction motifs and cover relatively larger interaction region, peptides are very promising as PPI inhibitors. To expedite drug discovery, computational approaches are widely used for screening potential lead compounds. Here, we developed peptides that inhibit mitochondrial fission 1 (Fis1)/mitochondrial dynamics 51 kDa (Mid51) PPI to reduce the cellular damage that can lead to various human pathologies, such as CVDs. Based on a rational design approach we developed peptide inhibitors of the Fis1/Mid51 PPI. In silico and in vitro studies were done to evaluate the biological activity and molecular interactions of the peptides. Two peptides, CVP-241 and CVP-242 were identified based on low binding energy and molecular dynamics simulations. These peptides inhibit Fis1/Mid51 PPI (-1324.9 kcal mol-1) in docking calculations (CVP-241, -741.3 kcal mol-1, and CVP-242, -747.4 kcal mol-1), as well as in vitro experimental studies Fis1/Mid51 PPI (KD 0.054 µM) Fis1/Mid51 PPI + CVP-241 (KD 3.43 µM), and Fis1/Mid51 PPI + CVP-242 (KD 44.58 µM). Finally, these peptides have no toxicity to H9c2 cells, and they increase cell viability in cardiomyocytes (H9c2 cells). Consequently, the identified inhibitor peptides could serve as potent molecules in basic research and as leads for therapeutic development.

| S-EPMC10773907 | biostudies-literature

Integrins protect cardiomyocytes from ischemia/reperfusion injury.

Project description:Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of ?7?1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of ?1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin ?7?1D exposed to I/R had a substantial reduction in infarct size compared with that of ?5?1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that ?7?1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that ?1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that ?7?1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.

| S-EPMC3784521 | biostudies-literature

Hypoxic extracellular vesicles from hiPSCs protect cardiomyocytes from oxidative damage by transferring antioxidant proteins and enhancing Akt/Erk/NRF2 signaling

Project description: Not available

| S-EPMC11232324 | biostudies-literature

Current Therapies for Neonatal Hypoxic-Ischaemic and Infection-Sensitised Hypoxic-Ischaemic Brain Damage.

Project description:Neonatal hypoxic-ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic-ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic-ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic-ischaemic brain injury. Models of neonatal hypoxia-ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18-22 months, is approximately 6-7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.

| S-EPMC8421799 | biostudies-literature

Platelets mediate cytotoxic T lymphocyte-induced liver damage.

Project description:We found that platelet depletion reduces intrahepatic accumulation of virus-specific cytotoxic T lymphocytes (CTLs) and organ damage in mouse models of acute viral hepatitis. Transfusion of normal but not activation-blocked platelets in platelet-depleted mice restored accumulation of CTLs and severity of disease. In contrast, anticoagulant treatment that prevented intrahepatic fibrin deposition without reducing platelet counts did not avert liver injury. Thus, activated platelets contribute to CTL-mediated liver immunopathology independently of procoagulant function.

| S-EPMC2908083 | biostudies-literature

RhoA regulates Drp1 mediated mitochondrial fission through ROCK to protect cardiomyocytes.

Project description:Cardiac ischemia/reperfusion, loss of blood flow and its subsequent restoration, causes damage to the heart. Oxidative stress from ischemia/reperfusion leads to dysfunction and death of cardiomyocytes, increasing the risk of progression to heart failure. Alterations in mitochondrial dynamics, in particular mitochondrial fission, have been suggested to play a role in cardioprotection from oxidative stress. We tested the hypothesis that activation of RhoA regulates mitochondrial fission in cardiomyocytes. Our studies show that expression of constitutively active RhoA in cardiomyocytes increases phosphorylation of Dynamin-related protein 1 (Drp1) at serine-616, and leads to localization of Drp1 at mitochondria. Both responses are blocked by inhibition of Rho-associated Protein Kinase (ROCK). Endogenous RhoA activation by the GPCR agonist sphingosine-1-phosphate (S1P) also increases Drp1 phosphorylation and its mitochondrial translocation in a RhoA and ROCK dependent manner. Consistent with the role of mitochondrial Drp1 in fission, RhoA activation in cardiomyocytes leads to formation of smaller mitochondria and this is attenuated by inhibition of ROCK, by siRNA knockdown of Drp1 or by expression of a phosphorylation-deficient Drp1 S616A mutant. In addition, activation of RhoA prevents cell death in cardiomyocytes challenged by oxidative stress and this protection is blocked by siRNA knockdown of Drp1 or by Drp1 S616A expression. Taken together our findings demonstrate that RhoA activation can regulate Drp1 to induce mitochondrial fission and subsequent cellular protection, implicating regulation of fission as a novel mechanism contributing to RhoA-mediated cardioprotection.

| S-EPMC6361616 | biostudies-literature

Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischaemic injury

Project description:Near-complete reversal of ERBB2-driven cardiomyocyte dedifferentiation is driven by the Hippo pathway, restoring contractility whilst long-lasting conferring cardioprotection.

2023-02-01 | PXD038450 | Pride

M2b macrophages protect against doxorubicin induced cardiotoxicity via alternating autophagy in cardiomyocytes.

Project description:ObjectiveDoxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential therapeutic application. The underlying mechanism of DOX induced cardiotoxicity is complex and remains elusive. Our previous studies have shown that M2b macrophage plays an important role in reducing inflammation due to ischemic reperfusion injury in the myocardium. The purpose of this study was to investigate the potential protective role of M2b macrophages in DOX induced cardiotoxicity.MethodsIn vivo, we conducted DOX induced cardiac injury in C57BL/6 mice and treated them with M2b macrophages. Then, the mice were examined by echocardiography. The heart specimens were harvested for histological examination, transmission electron microscope analysis, and autophagy molecules evaluation. In vitro, HL-1 cardiac cell lines treated with DOX were cocultured with or without M2b macrophages. Then, Autophagy related genes and protein expression were assessed by real-time quantitative PCR and western blot; cell proliferation was assessed by cell counting kit-8.ResultsWe found that M2b macrophages can improve cardiac function and alleviate cardiac injury in DOX induced cardiac injury mice. M2b macrophages can enhance cardiac autophagy levels both in vivo and in vitro in DOX induced cardiac injury model. In addition, this protective effect can be blocked by an autophagy inhibitor.ConclusionOur study shows that M2b macrophages can help attenuate the DOX induced cardiotoxicity by regulating the autophagy level of cardiomyocytes.

| S-EPMC10374082 | biostudies-literature

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