Relevance of stromal interaction molecule 1 (STIM1) in experimental and human stroke

2021 ◽  
Author(s):  
Rosita Stanzione ◽  
Maurizio Forte ◽  
Maria Cotugno ◽  
Franca Bianchi ◽  
Simona Marchitti ◽  
...  
Keyword(s):  
Stromal Interaction Molecule 1 ◽  
Human Stroke

scholarly journals Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke

2021 ◽  
Author(s):  
Alexander M. Kollikowski ◽  
Mirko Pham ◽  
Alexander G. März ◽  
Lena Papp ◽  
Bernhard Nieswandt ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Platelet Activation ◽  
Prospective Observational Study ◽  
Self Control ◽  
Anterior Circulation ◽  
Vessel Occlusion ◽  
Platelet Counts ◽  
Arterial Blood ◽  
Human Stroke ◽  
Leukocyte Counts

AbstractExperimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018–05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (− 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r =  − 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization.

scholarly journals Isolation and identification of leukocyte populations in intracranial blood collected during mechanical thrombectomy

2021 ◽  
pp. 0271678X2110284
Author(s):  
Benjamin C Shaw ◽  
G Benton Maglinger ◽  
Thomas Ujas ◽  
Chintan Rupareliya ◽  
Justin F Fraser ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Small Volume ◽  
Mechanical Thrombectomy ◽  
Isolation And Identification ◽  
Systemic Blood ◽  
Arterial Blood ◽  
Edema Volume ◽  
Human Stroke ◽  
Leukocyte Populations ◽  
Standard Techniques

Using standard techniques during mechanical thrombectomy, the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (NCT03153683) isolates intracranial arterial blood distal to the thrombus and proximal systemic blood in the carotid artery. We augmented the current protocol to study leukocyte subpopulations both distal and proximal to the thrombus during human stroke (n = 16 patients), and from patients with cerebrovascular disease (CVD) undergoing angiography for unrelated conditions (e.g. carotid artery stenosis; n = 12 patients). We isolated leukocytes for flow cytometry from small volume (<1 mL) intracranial blood and systemic blood (5–10 mL) to identify adaptive and innate leukocyte populations, in addition to platelets and endothelial cells (ECs). Intracranial blood exhibited significant increases in T cell representation and decreases in myeloid/macrophage representation compared to within-patient carotid artery samples. CD4+ T cells and classical dendritic cells were significantly lower than CVD controls and correlated to within-patient edema volume and last known normal. This novel protocol successfully isolates leukocytes from small volume intracranial blood samples of stroke patients at time of mechanical thrombectomy and can be used to confirm preclinical results, as well as identify novel targets for immunotherapies.

Atomic force microscopy (AFM) imaging suggests that stromal interaction molecule 1 (STIM1) binds to Orai1 with sixfold symmetry

FEBS Letters ◽  
2014 ◽  
Vol 588 (17) ◽  
pp. 2874-2880 ◽  
Author(s):  
Dilshan Balasuriya ◽  
Shyam Srivats ◽  
Ruth D. Murrell-Lagnado ◽  
J. Michael Edwardson
Keyword(s):  
Atomic Force Microscopy ◽  
Force Microscopy ◽  
Stromal Interaction Molecule 1 ◽  
Atomic Force ◽  
Afm Imaging ◽  
Sixfold Symmetry

scholarly journals X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shaohua Qi ◽  
Abdullah Al Mamun ◽  
Conelius Ngwa ◽  
Sharmeen Romana ◽  
Rodney Ritzel ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
X Chromosome ◽  
Epigenetic Modification ◽  
Artery Occlusion ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Young Females ◽  
Human Stroke ◽  
Histone H3k4 ◽  
Cerebral Artery Occlusion

Abstract Background Stroke is a sexually dimorphic disease. Previous studies have found that young females are protected against ischemia compared to males, partially due to the protective effect of ovarian hormones, particularly estrogen (E2). However, there are also genetic and epigenetic effects of X chromosome dosage that contribute to stroke sensitivity and neuroinflammation after injury, especially in the aged. Genes that escape from X chromosome inactivation (XCI) contribute to sex-specific phenotypes in many disorders. Kdm5c and kdm6a are X escapee genes that demethylate H3K4me3 and H3K27me3, respectively. We hypothesized that the two demethylases play critical roles in mediating the stroke sensitivity. Methods To identify the X escapee genes involved in stroke, we performed RNA-seq in flow-sorted microglia from aged male and female wild type (WT) mice subjected to middle cerebral artery occlusion (MCAO). The expression of these genes (kdm5c/kdm6a) were confirmed in four core genotypes (FCG) mice and in post-mortem human stroke brains by immunohistochemistry (IHC), Western blot, and RT-PCR. Chromatin immunoprecipitation (ChIP) assays were conducted to detect DNA levels of inflammatory interferon regulatory factor (IRF) 4/5 precipitated by histone H3K4 and H3K27 antibodies. Manipulation of kdm5c/kdm6a expression with siRNA or lentivirus was performed in microglial culture, to determine downstream pathways and examine the regulatory roles in inflammatory cytokine production. Results Kdm5c and kdm6a mRNA levels were significantly higher in aged WT female vs. male microglia, and the sex difference also existed in ischemic brains from FCG mice and human stroke patients. The ChIP assay showed the IRF 4/5 had higher binding levels to demethylated H3K4 or H3K27, respectively, in female vs. male ischemic microglia. Knockdown or over expression of kdm5c/kdm6a with siRNA or lentivirus altered the methylation of H3K4 or H3K27 at the IRF4/5 genes, which in turn, impacted the production of inflammatory cytokines. Conclusions The KDM-Histone-IRF pathways are suggested to mediate sex differences in cerebral ischemia. Epigenetic modification of stroke-related genes constitutes an important mechanism underlying the ischemic sexual dimorphism.

Abstract WP281: Incorporating Biological Variability in Experimental Stroke to Better Mimic Human Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Thomas A Kent ◽  
Harriett C Rea ◽  
William Dalmeida ◽  
Roderic H Fabian ◽  
Cenk Ayata ◽  
...  
Keyword(s):  
Middle Surface ◽  
Lower Surface ◽  
Clinical Results ◽  
Experimental Stroke ◽  
Biological Variability ◽  
Occlusion Time ◽  
Physiological Variability ◽  
Functional Measure ◽  
Stroke Models ◽  
Human Stroke

Introduction: Failures to translate pre-clinical results have been discouraging. We have contended that stroke is too heterogeneous with respect to factors influencing outcome to expect small studies to be balanced. It is not only difficult to control for biological and methodological variability but efforts to improve homogeneity, such as minimizing physiological variability, may render results less applicable to humans. Here, we report a predictive outcome model in experimental stroke which incorporates baseline variability and provides statistical thresholds a treatment must exceed to be efficacious in a broad population. Methods: We generated a mathematical model to predict outcome using transient MCA occlusion in 23 unfasted rats. To create baseline variability, we varied occlusion times from 90-120 min, altered baseline glucose with streptozotocin, and assessed neurological outcome 3 days later with a modified Bederson Score (BS; 0-6 functional measure, 7 death). Statistical surfaces in 3 dimensions were generated using Jacobian matrices flanking the model to provide a screening threshold (1 SD) for comparing new therapies against this model. Results: We successfully generated an outcome model from occlusion time, glucose and BS (Fig; R 2 =.49, p=.0003; middle surface is the model surrounded by ±SD surfaces). Outcome was sensitive to change in glucose and time, suggesting small imbalances in these factors between groups may influence outcome, and hence the perceived efficacy of a new therapeutic intervention. At normoglycemia and 90 mins, the lower surface overlapped with no deficit, indicating it would be difficult to reliably demonstrate benefit under those conditions. Conclusions: These results indicate it is feasible to incorporate biological variability to generate more clinically relevant conditions. The method will be tested with other stroke models and modifiers towards a generalized model to screen for therapies worthy of further study.

Does stromal interaction molecule-1 have five senses?

Cell Calcium ◽  
2019 ◽  
Vol 77 ◽  
pp. 79-80 ◽  
Author(s):  
Peter B. Stathopulos ◽  
Mitsuhiko Ikura
Keyword(s):  
Stromal Interaction Molecule 1 ◽  
Five Senses

scholarly journals Genetically-Defined Deficiency of Mannose-Binding Lectin Is Associated with Protection after Experimental Stroke in Mice and Outcome in Human Stroke

PLoS ONE ◽  
2010 ◽  
Vol 5 (2) ◽  
pp. e8433 ◽  
Author(s):  
Alvaro Cervera ◽  
Anna M. Planas ◽  
Carles Justicia ◽  
Xabier Urra ◽  
Jens C. Jensenius ◽  
...  
Keyword(s):  
Mannose Binding Lectin ◽  
Experimental Stroke ◽  
Mannose Binding ◽  
Human Stroke ◽  
Binding Lectin

scholarly journals Novel role of the ER/SR Ca2+ sensor STIM1 in the regulation of cardiac metabolism

2019 ◽  
Vol 316 (5) ◽  
pp. H1014-H1026 ◽  
Author(s):  
Helen E. Collins ◽  
Betty M. Pat ◽  
Luyun Zou ◽  
Silvio H. Litovsky ◽  
Adam R. Wende ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Pyruvate Dehydrogenase ◽  
Glucose Utilization ◽  
Cardiac Metabolism ◽  
Mitochondrial Morphology ◽  
Acid Uptake ◽  
Stromal Interaction Molecule 1 ◽  
First Time

The endoplasmic reticulum/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca2+ entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (crSTIM1-KO) results in age-dependent endoplasmic reticulum stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-wk-old crSTIM1-KO mice exhibited a significant reduction in both oxidative and nonoxidative glucose utilization. Consistent with the reduction in glucose utilization, expression of glucose transporter 4 and AMP-activated protein kinase phosphorylation were all reduced, whereas pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphorylation were increased, in crSTIM1-KO hearts. Despite similar rates of fatty acid oxidation in control and crSTIM1-KO hearts ex vivo, crSTIM1-KO hearts contained increased lipid/triglyceride content as well as increased fatty acid-binding protein 4, fatty acid synthase, acyl-CoA thioesterase 1, hormone-sensitive lipase, and adipose triglyceride lipase expression compared with control hearts, suggestive of a possible imbalance between fatty acid uptake and oxidation. Insulin-mediated alterations in AKT phosphorylation were observed in crSTIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wk crSTIM1-KO hearts, suggesting that these changes may initiate the subsequent metabolic dysfunction. These results demonstrate, for the first time, that cardiomyocyte STIM1 may play a key role in regulating cardiac metabolism. NEW & NOTEWORTHY Little is known of the physiological role of stromal interaction molecule 1 (STIM1) in the heart. Here, we demonstrate, for the first time, that hearts lacking cardiomyocyte STIM1 exhibit dysregulation of both cardiac glucose and lipid metabolism. Consequently, these results suggest a potentially novel role for STIM1 in regulating cardiac metabolism.

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