CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Kim E
PROVIDER: S-EPMC3383818 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hyperlipidemia with accompanying increase in peripheral inflammation is a risk factor for stroke. The effect of excess lipids on stroke-induced injury and the mechanism by which lipid-mediated inflammatory responses contribute to stroke are not known. We investigated these uncertainties by subjecting normal and hyperlipidemic mice to transient middle cerebral artery occlusion, followed by measurement of stroke severity and inflammatory response. Infarct size, swelling, and lipid contents were significantly increased in the high-fat fed ApoE knock-out mice, as was the expression of the inflammatory mediators CD36 and monocyte chemoattractant protein 1 (MCP-1) in the brain and periphery. Furthermore, the hyperlipidemic mice exhibited numerous foam cells, a probable cause of increased swelling and postischemic inflammation, in the peri-infarct area. Genetic deletion of cd36 in the hyperlipidemic condition reduced proinflammatory chemokine/receptor and cytokines (MCP-1, CC chemokine receptor 2, and interleukins 1beta and 6), in the brain 6 h after ischemia. The reduced proinflammatory response also resulted in smaller ischemic injury, less swelling, and fewer foam cells at 3 d after ischemia. The results show that hyperlipidemia-induced inflammation is a negative factor for stroke outcomes and indicate that downregulating CD36 may be an effective therapeutic strategy for reducing the impact of stroke in hyperlipidemic subjects.
| S-EPMC2830708 | biostudies-literature
Project description:AimsThe pathology of stroke consists of multiple pro-death processes, and CD36 has been suggested as a multimodal target to reduce oxidative stress and inflammation in ischemic stroke. Using CD36-deficient mice and SS-31, a cell permeable tetrapeptide known to down-regulate CD36 pathways, the current study investigated whether targeting CD36 is effective in transient and permanent ischemic stroke.MethodsWild-type or CD36-deficient mice were subjected to either 30-min transient or permanent focal ischemic stroke. In parallel, a cohort of mice subjected to either transient or permanent stroke received either vehicle or 5 mg/kg of SS-31. Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2, mRNA levels, and infarct volume and percent hemispheric swelling were measured in the postischemic brain.ResultsCD36 deficiency or SS-31 treatment significantly attenuated MCP-1 or CCR2 mRNA up-regulation and injury size in the transient ischemic stroke. However, the approaches failed to show the protective effect in permanent ischemic stroke.ConclusionThe study revealed that targeting CD36 has a beneficial effect on transient but not permanent focal ischemic stroke. The study thus precludes a generalized strategy targeting CD36 in ischemic stroke and suggests careful consideration of types of stroke and associated pathology in developing stroke therapies.
| S-EPMC4362808 | biostudies-literature
Project description:OBJECTIVE:The scavenger receptor CD36 is injurious in acute experimental focal stroke and neurodegenerative diseases in the adult. We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke. METHODS:Postnatal day 9 CD36ko and wild-type (WT) mice were subjected to a transient middle cerebral artery occlusion (MCAO). Injury, phagocytosis of dying cells, and CD36 inflammatory signaling were determined. RESULTS:While the volume of tissue at risk by diffusion-weighted magnetic resonance imaging during MCAO was similar in neonatal CD36ko and WT mice, by 24 hours after reperfusion, injury was more severe in CD36ko and was associated with increased caspase-3 cleavage and reduced engulfment of neurons expressing cleaved caspase-3 by activated microglia. No significant superoxide generation was observed in activated microglia in injured WT, whereas increased superoxide production in vessels and nuclear factor (NF)-?B activation induced by MCAO were unaffected by lack of CD36. Lyn expression was higher in injured CD36ko, and cell type-specific patterns of Lyn expression were altered; Lyn was expressed in endothelial cells and microglia in WT but predominantly in dying neurons in CD36ko. INTERPRETATION:Lack of CD36 results in poorer short-term outcome from neonatal focal stroke due to lack of attenuation of NF-?B-mediated inflammation and diminished removal of apoptotic neuronal debris. Although inhibition of CD36 does not seem to be a good therapeutic target for protection after acute neonatal stroke, as it is after adult stroke, seeking better understanding of CD36 signaling in particular cell populations may reveal important therapeutic targets for neonatal stroke.
| S-EPMC3539222 | biostudies-literature
Project description:CD36 expressed in multiple cell types regulates inflammation, vascular function, and innate immunity. Specifically, CD36 in microvascular endothelial cells (ECs) signals to elicit inflammation and causes EC death. This study investigated roles for EC-CD36 on acute stroke pathology in normal and obese conditions. Obesity induced by a high-fat diet (HD) selectively increased CD36 expression in ECs, not in monocytes/macrophages, in the post-ischemic brain. Mice deficient CD36 in ECs (ECCD36-/-) showed reduced injury size and vascular permeability in normal conditions. While control mice fed a HD developed obesity and aggravated stroke injury, ECCD36-/- mice were resistant to develop an obesity phenotype. Subjecting ECCD36-/- mice to stroke resulted in reduced injury size and BBB disruption. Moreover, the mice had reduced MCP-1 and CCR2 gene expression, resulting in reduced monocyte trafficking with improved survival and acute motor function. Reduced MCP-1 and CCR2 expression was still evident in ECCD36-/- mice subjected to severe stroke, suggesting that monocyte trafficking is an infarct-independent metabolic effect associated with specific EC-CD36 deletion. Our findings demonstrate the importance of EC-CD36 in developing vascular comorbidities and suggest that targeting EC-CD36 is a potential preventative strategy to normalize vascular risk factors, leading to improved acute stroke outcomes.
| S-EPMC10196754 | biostudies-literature
Project description:Dyslipidemia is associated with a prothrombotic phenotype; however, the mechanisms responsible for enhanced platelet reactivity remain unclear. Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein. Using multiple mouse in vivo thrombosis models, we now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype. Structurally defined oxidized choline glycerophospholipids that serve as high-affinity ligands for CD36 were at markedly increased levels in the plasma of hyperlipidemic mice and in the plasma of humans with low HDL levels, were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36. Thus, interactions of platelet CD36 with specific endogenous oxidized lipids play a crucial role in the well-known clinical associations between dyslipidemia, oxidant stress and a prothrombotic phenotype.
| S-EPMC3042888 | biostudies-literature
Project description:Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.
| S-EPMC7496035 | biostudies-literature
Project description:Autofluorescence is frequently observed in animal tissues, interfering with an experimental analysis and leading to inaccurate results. Sudan black B (SBB) is a staining dye widely used in histological studies to eliminate autofluorescence. In this study, our objective was to characterize brain tissue autofluorescence present in three models of acute brain injury, including collagenase-induced intracerebral hemorrhage (ICH), traumatic brain injury (TBI), and middle cerebral artery occlusion, and to establish a simple method to block autofluorescence effectively. Using fluorescence microscopy, we examined autofluorescence in brain sections affected by ICH and TBI. In addition, we optimized a protocol to block autofluorescence with SBB pretreatment and evaluated the reduction in fluorescence intensity. Compared to untreated, pretreatment with SBB reduced brain tissue autofluorescence in the ICH model by 73.68% (FITC), 76.05% (Tx Red), and 71.88% (DAPI), respectively. In the TBI model, the ratio of pretreatment to untreated decreased by 56.85% (FITC), 44.28% (Tx Red), and 46.36% (DAPI), respectively. Furthermore, we tested the applicability of the protocol using immunofluorescence staining or Cyanine-5.5 labeling in the three models. SBB treatment is highly effective and can be applied to immunofluorescence and fluorescence label imaging techniques. SBB pretreatment effectively reduced background fluorescence but did not significantly reduce the specific fluorescence signal and greatly improved the signal-to-noise ratio of fluorescence imaging. In conclusion, the optimized SBB pretreatment protocol blocks brain section autofluorescence of the three acute brain injury models.
| S-EPMC10258339 | biostudies-literature
Project description:Traumatic brain injury (TBI) can lead to severe neurotrauma, leading to long-term cognitive decline and even death. Massive neuronal loss and excessive neuroinflammation are critical issues in the treatment of secondary TBI. To tackle these challenges, we developed a GelMA and CSMA hydrogel loaded with Erythropoietin (EPO) and Interleukin-4 (IL-4), named GC/I/E. By directly loading the hydrogel with EPO, rapid neuroprotection and angiogenesis were achieved. Meanwhile, by loading Mesoporous silica nanoparticles (MSNs) with IL-4 (MSN@IL-4), sustained inflammation modulation during inflammation was attained. In vitro experiments demonstrated that GC/I/E hydrogel were biocompatible and could provide neuroprotection for HT22 cells in H2O2 environment, regulate RAW264.7 polarization from M1 to M2 phenotype and promote HUVEC angiogenesis. In vivo experiments demonstrated that GC/I/E hydrogel reduced brain edema and Nissl body damage, inhibited inflammatory expression of G3-FFAP and neural scarring, improved microvascular and vascular function reconstruction, and facilitated neuronal and synaptogenesis, ultimately improving neurofunctional recovery in TBI. RNA sequencing results demonstrated that GC/I/E hydrogel treatment significantly correlated with the regulation of genes such as apoptosis, inflammation regulation, and neural regeneration. This bioactive hydrogel with neuroprotection, inflammation modulation and promotion of angiogenesis has great potential for TBI treatment.
| S-EPMC11609671 | biostudies-literature
Project description:Ischemic stroke prompts a strong inflammatory response, which is associated with exacerbated outcomes. In this study, we investigated mechanistic regulators of neutrophil extracellular trap (NET) formation in stroke and whether they contribute to stroke outcomes. NET-forming neutrophils were found throughout brain tissue of ischemic stroke patients, and elevated plasma NET biomarkers correlated with worse stroke outcomes. Additionally, we observed increased plasma and platelet surface-expressed high-mobility group box 1 (HMGB1) in stroke patients. Mechanistically, platelets were identified as the critical source of HMGB1 that caused NETs in the acute phase of stroke. Depletion of platelets or platelet-specific knockout of HMGB1 significantly reduced plasma HMGB1 and NET levels after stroke, and greatly improved stroke outcomes. We subsequently investigated the therapeutic potential of neonatal NET-inhibitory factor (nNIF) in stroke. Mice treated with nNIF had smaller brain infarcts, improved long-term neurological and motor function, and enhanced survival after stroke. nNIF specifically blocked NET formation without affecting neutrophil recruitment after stroke. Importantly, nNIF also improved stroke outcomes in diabetic and aged mice and was still effective when given 1 hour after stroke onset. These results support a pathological role for NETs in ischemic stroke and warrant further investigation of nNIF for stroke therapy.
| S-EPMC9106355 | biostudies-literature
Project description:ObjectiveTo investigate the effects of peroxisome proliferator-activated receptor (PPAR)δ in the cerebral vasculature following stroke-induced brain injury.Methods and resultsHere, we report a novel finding that selective PPARδ genetic deletion in vascular smooth muscle cells (VSMCs) resulted in increased cerebrovascular permeability and brain infarction in mice after middle cerebral artery occlusion (MCAO). Mechanistically, we revealed for the first time that PPARδ expression is reduced, but matrix metalloproteinase (MMP)-9 activity is increased in cultured VSMCs after oxygen-glucose deprivation and also in the cerebral cortex of mice following MCAO. Moreover, gain- and loss of PPARδ function in VSMCs significantly reduces and increases oxygen-glucose deprivation-induced MMP-9 activity, respectively. We have further identified that MMP-9 is a direct target of PPARδ-mediated transrepression by chromatin immunoprecipitation and PPARδ transcriptional activity assays. Furthermore, inhibition of MMP-9 activity by lentiviral MMP-9 short hairpin RNA effectively improves cerebrovascular permeability and reduces brain infarction in VSMC-selective PPARδ conditional knockout mice after MCAO.ConclusionsOur data demonstrate that PPARδ in VSMCs can prevent ischemic brain injury by inhibition of MMP-9 activation and attenuation of postischemic inflammation. The pharmacological activation of PPARδ may provide a new therapeutic strategy to treat stroke-induced vascular and neuronal damage.
| S-EPMC3291895 | biostudies-literature