RESUMO
The endothelial-mesenchymal transition (EndMT) is involved in the development of atherosclerosis (AS) and is a key process in vascular endothelial injury. Oxidative stress, inflammation, and apoptosis are common causes of EndMT, and EndMT progression can further accelerate the development of AS. The metabolite trimethylamine N-oxide (TMAO) is produced by the gut microbiome and is implicated in the development of several diseases, including diabetes and chronic kidney disease. However, the impact of TMAO on transforming growth factor ß1(TGF-ß1)-induced EndMT remains unclear. We hypothesize that TMAO exacerbates plaque formation and cardiac function impairment by promoting EndMT. Herein, we showed that high serum TMAO levels caused plaque formation, cardiac function damage and haemodynamic changes in ApoE-/- mice. In vitro, TMAO upregulated mesenchymal markers and downregulated endothelial markers in HAECs. Furthermore, TMAO increased the migratory capacity of EndMT cells. Mechanistically, we found that PERK downregulation could alleviate TMAO-induced oxidative stress, EndMT, plaque formation and cardiac function damage. Further study showed that activated transcription factor 3 (ATF3), the downstream molecule of protein kinase RNA-like endoplasmic reticulum kinase (PERK), could bind with TGF-ß1/2 and affect EndMT. Overall, TMAO promotes EndMT, possibly through the PERK-eIF2α-ATF4-CHOP or the PERk-eIF2α-ATF3-TGF-ß signalling pathways.
Assuntos
Apoptose , Aterosclerose , Metilaminas , eIF-2 Quinase , Animais , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Apoptose/efeitos dos fármacos , Camundongos , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Cultivadas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Camundongos Knockout para ApoE , Fator 3 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/genética , Transição Endotélio-MesênquimaRESUMO
Chromatin regulators are indispensable upstream epigenetic regulators.The emergence and progression of atherosclerosis has been demonstrated to be influenced by smooth muscle-related chromatin regulators, such as ZEB2 and MAFF. However, specific chromatin regulators and their possible roles have not been clarified. Information was gathered from 51 patients diagnosed with coronary artery disease (CAD) and 50 individuals in good health from the GEO database. 440 genes were identified as having differential expression across the two datasets, and these genes were linked to cellular reactions. Enrichment of pathways related to histone modification and transcriptional regulatory factors was observed in GO and KEGG analyses. Four machine learning models (RF, SVM, GLM, and XGB) were developed using the expression profiles of 440 chromatin-associated genes in the CAD cohort to pinpoint genes with significant diagnostic potential. After evaluating residuals, root mean square errors, receiver operating characteristic curves, and immune-infiltration, four key genes (HCFC1, RNF8, TNP1, and SET) were identified. Gene expression in different blood vessel levels in atherosclerotic plaques in a mouse model of coronary artery disease showed significant variations. The gene expression levels in macrophages aligned with clinical data from the GEO database as expected. This discovery is crucial for future analysis and the prediction of drug and miRNA targets. In conclusion, we found that the four hub genes are important in the mechanism of CAD. These findings provide new ideas for the study of potential epigenetic predictive markers and therapeutic targets to be used in determining a treatment strategy for CAD.
RESUMO
Liver fibrosis is the common pathological change of chronic liver diseases characterized by increased deposition of extracellular matrix and reduced matrix degradation. In response to liver injury caused by a variety of pathogenic agents, such as virus and alcohol, hepatic stellate cells (HSCs) are differentiated into myofibroblast-like cells and produce excessive collagens, thus resulting in fibrogenesis. Natural killer (NK) cells are the essential innate immune cells in the liver and generally control fibrosis by killing activated HSCs. This review briefly describes the fibrogenesis process and the phenotypic features of hepatic NK cells. Besides, it focuses on the antifibrotic mechanisms of NK cells and explores the potential of activating NK cells as a therapeutic strategy for the disease.