RESUMO
Atherosclerotic plaque instability is a major cause of ischemic stroke. Researchers must develop novel strategies for the detection and treatment of unstable atherosclerotic plaque (UAP)-related stroke. We aimed to identify potential biomarkers and therapeutic targets of UAP-related stroke. Differentially expressed genes (DEGs) of UAP, ischemic stroke and smoking were identified by microarray analyses from the Gene Expression Omnibus. Gene Ontology (GO) and pathway functional enrichment analyses of DEGs were performed to analyze plaque destabilization and ischemic stroke physiopathology. An integrative analysis of UAP, ischemic stroke and smoking DEGs and functional annotations was performed to identify the underlying physiopathology and hub genes in UAP-related stroke and the relationship with smoking. Online search databases were applied to confirm hub gene biofunctions and their relationships with atherosclerosis and cerebrovascular diseases. Following integrative analysis, 18 co-DEGs of UAP and ischemic stroke, including 17 upregulated and one downregulated, were identified. Inflammation, immunity, extracellular matrix degradation, blood coagulation, apoptosis and nerve degeneration were the primary physiopathological processes in UAP-related stroke. Hub genes included MMP9, ITGAM, CCR1, NCF2 and CD163, among which MMP9 and ITGAM were top 10 genes for both UAP and stroke. Smoking may upregulate MMP9, NCF2, C5AR1 and ANPEP to accelerate plaque destabilization and UAP-related stroke. MMP9, ITGAM, CCR1, NCF2, CD163, hsa-miR-3123 and hsa-miR-144-3p are potential diagnostic and prognostic biomarkers of UAP-related stroke. MMP9 and ITGAM are potential therapeutic targets of UAP-related stroke, which will contribute to the development of novel management strategies.
Assuntos
Loci Gênicos , Predisposição Genética para Doença , AVC Trombótico/genética , Biomarcadores/metabolismo , Biologia Computacional , Humanos , Terapia de Alvo Molecular , Fumar/epidemiologia , AVC Trombótico/tratamento farmacológico , AVC Trombótico/epidemiologia , TranscriptomaRESUMO
RATIONALE: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Recanalization of the occluded vessel is essential but not sufficient to guarantee brain salvage. Experimental and clinical data suggest that infarcts often develop further due to a thromboinflammatory process critically involving platelets and T cells, but the underlying mechanisms are unknown. OBJECTIVE: We aimed to determine the role of CD (cluster of differentiation)-84 in acute ischemic stroke after recanalization and to dissect the underlying molecular thromboinflammatory mechanisms. METHODS AND RESULTS: Here, we show that mice lacking CD84-a homophilic immunoreceptor of the SLAM (signaling lymphocyte activation molecule) family-on either platelets or T cells displayed reduced cerebral CD4+ T-cell infiltration and thrombotic activity following experimental stroke resulting in reduced neurological damage. In vitro, platelet-derived soluble CD84 enhanced motility of wild-type but not of Cd84-/- CD4+ T cells suggesting homophilic CD84 interactions to drive this process. Clinically, human arterial blood directly sampled from the ischemic cerebral circulation indicated local shedding of platelet CD84. Moreover, high platelet CD84 expression levels were associated with poor outcome in patients with stroke. CONCLUSIONS: These results establish CD84 as a critical pathogenic effector and thus a potential pharmacological target in ischemic stroke.
Assuntos
Plaquetas/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , AVC Trombótico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Coagulação Sanguínea , Linfócitos T CD4-Positivos/imunologia , Quimiotaxia de Leucócito , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/imunologia , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estudos Prospectivos , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , AVC Trombótico/genética , AVC Trombótico/imunologiaRESUMO
We recently reported that upregulation of the constitutively active ras homolog enriched in brain [Rheb(S16H)], which induces the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, can protect adult neurons, mediated by the induction of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in animal models of neurodegenerative diseases. Here we show that neuronal transduction of Rheb(S16H) using adeno-associated virus serotype 1 provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke. Rheb(S16H)-expressing neurons exhibited neurotrophic effects, such as mTORC1 activation, increases in neuronal size, and BDNF production, in mouse cerebral cortex. Moreover, the upregulation of neuronal Rheb(S16H) significantly attenuated ischemic damage and behavioral impairments as compared to untreated mice, suggesting that Rheb(S16H) upregulation in cortical neurons may be a useful strategy to treat ischemic stroke.
