Biology subjects

Zhong, L.

Publications and source records attributed to Zhong, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Key genes and pathways in asparagine metabolism in Alzheimers Disease: a bioinformatics approach

BackgroundAsparagine (Asn) metabolism is essential for maintaining cellular homeostasis and supporting neuronal energy demands. Recent studies have suggested its dysregulation may contribute to Alzheimers disease (AD) pathogenesis; however, the specific genes and regulatory mechanisms involved remain incompletely understood. MethodsFour publicly available microarray datasets (GSE5281, GSE29378, GSE36980, and GSE138260) were utilized to investigate genes with differential expression between control and AD samples. Asparagine metabolism-related genes (AMGs) were retrieved from the GeneCards database, and their intersection with DEGs yielded candidate asparagine metabolism-related differentially expressed genes (AMG-DEGs). Functional enrichment analysis (Gene Set Enrichment Analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes), protein-protein interaction (PPI) network analysis, and centrality scoring identified hub genes. Regulatory mechanisms were investigated through construction of competing endogenous RNA and transcription factor networks. Potential therapeutic compounds were predicted via drug-gene enrichment and evaluated using molecular docking simulations. ResultsThirty-nine AMG-DEGs were identified and found to be enriched in neurodevelopmental, synaptic transmission, and inflammatory signaling pathways. PPI analysis and centrality screening revealed seven hub genes (HPRT1, GAD2, TUBB3, GFAP, CD44, CCL2, and NFKBIA). Regulatory network analysis highlighted specific miRNAs, long non-coding RNAs, and transcription factors involved in their modulation. Drug screening and docking identified Bathocuproine disulfonate, DL-Mevalonic acid, and Phenethyl isothiocyanate as promising compounds with strong binding affinities to hub proteins. ConclusionThis study comprehensively maps the dysregulation of asparagine metabolism in Alzheimers disease and reveals a set of hub genes and regulatory elements potentially involved in disease progression. The predicted therapeutic compounds provide a foundation for further experimental validation and may contribute to the development of novel metabolism-targeted strategies for AD treatment.

neuroscience↗

bioRxiv2025

Explosive cytotoxicity of 'ruptoblasts' bridges hormonal surveillance and immune defense

Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells - T cells, natural killer cells, and neutrophils. Here, we identify ruptoblasts, a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, ruptosis, triggered by activin, a multifunctional hormone that also acts as an inflammatory cytokine. Excessive activin - induced through protein injection, genetic chimerism, or bacterial infection - initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating any nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic mechanisms, the explosive nature of ruptosis relies on intracellular calcium and dynamic cytoskeletal reorganization. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a widespread strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.

immunology↗

bioRxiv2025

SpaFun: Discovering Domain-specific Spatial Expression Patterns and New Disease-Relevant Genes using Functional Principal Component Analysis

SpaFun is a novel, non-model-based method developed to address limitations in existing spatially variable gene (SVG) detection techniques, particularly for large-scale spatially resolved transcriptomics (SRT) datasets. These limitations include computational inefficiency, limited statistical power with increasing data size, and the inability to capture spatial heterogeneity and co-expression patterns among genes. Built on functional principal component analysis (fPCA), SpaFun identifies domain-representative genes (DRGs) with significantly better computational efficiency and greater statistical power while accounting for spatial heterogeneity and co-expression patterns among genes. We applied SpaFun to three SRT datasets and demonstrated that SpaFun outperformed state-of-the-art algorithms for identifying representative genes for tumor regions (e.g., DESeq, edgeR, and limma), as well as recently developed novel algorithms designed for spatial omics to identify the representative genes (e.g., SPARK and CSIDE). This highlights SpaFuns ability to accurately identify genes most representative of each spatial domain (e.g., tumor, immune, or stroma regions). By uncovering novel disease-relevant genes overlooked by existing algorithms, SpaFun could provide insights into new molecular mechanisms and propose innovative therapeutic strategies to improve patient outcomes. Key PointsO_LISpaFun is the first method dedicated to identifying DRGs, capturing spatially representative expression patterns within annotated tissue regions, setting it apart from all traditional SVG detection methods. C_LIO_LIIt leverages fPCA to model gene expression as a function of spatial location, avoiding reliance on predefined spatial distribution assumptions. C_LIO_LIThe non-model-based framework ensures compatibility with different SRT platforms and experimental designs, making it a scalable and widely applicable tool for SRT research. C_LI

genomics↗

bioRxiv2025

In situ generated vaccine-like pyroptosome for personalized cancer immunotherapy

The efficacy of in situ cancer vaccination has been hampered by poor spatiotemporal orchestration of multiple key steps of cancer-immunity cycle in most tumours and systemic toxicity related to therapeutic strategies. Here, we report a systemic injectable and pyroptosis-enabled nanoadjuvant (SPEN) that precisely evokes the secretion of vaccine-like pyroptosome in tumour area for eliciting robust anti-tumour immunity. SPEN induces vigorous immunogenic pyroptosis, triggering the efficient release of tumour antigen-rich pyroptosomes, DAMPs, and proinflammatory cytokines. Upon the activatable release of a TLR7/8 agonist into pyroptosome, the generated pyroptosome functions as in situ cancer vaccine for cooperatively activating the cancer-immunity cycle while avoiding systemic toxicity. This in situ vaccine boosts both innate and adaptive immune response, facilitating the eradication of primary tumour and long-lasting cancer prevention. Our findings provide new insights into the rational design of pyroptosis-inducing nanomedicines for boosting the cancer-immunity cycle, thus advancing personalized cancer immunotherapy.

cancer biology↗

bioRxiv2025

A critical initialization for biological neural networks

Artificial neural networks learn faster if they are initialized well. Good initializations can generate high-dimensional macroscopic dynamics with long timescales. It is not known if biological neural networks have similar properties. Here we show that the eigenvalue spectrum and dynamical properties of large-scale neural recordings in mice (two-photon and electrophysiology) are similar to those produced by linear dynamics governed by a random symmetric matrix that is critically normalized. An exception was hippocampal area CA1: population activity in this area resembled an efficient, uncorrelated neural code, which may be optimized for information storage capacity. Global emergent activity modes persisted in simulations with sparse, clustered or spatial connectivity. We hypothesize that the spontaneous neural activity reflects a critical initialization of whole-brain neural circuits that is optimized for learning time-dependent tasks.

neuroscience↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗

bioRxiv2024

Computational Identification of Migrating T cells in Spatial Transcriptomics Data

T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.

bioinformatics↗

bioRxiv2024

A multidimensional Pan-cancer analysis of CDKN1A identifies CDKN1A as an Immunological and Prognostic Biomarker

CDKN1A/p21 is well recognized for its role in cell cycle regulation and genomic stability. However, its functions in the Tumor microenvironment (TME) and tumor immunity are not yet fully understood. Hereby, we explored CDKN1A expression and immunological/prognostic values via various databases and analytical methods including cBioPortal, Kaplan-Meier, UCSCXenaShiny, TIMER, Single-cell RNA sequencing (scRNA-seq) analysis, etc. In addition, we explored different approaches including CCK8, EdU, Colony formation, Drug sensitivity and Annixin-V assay to explore the influence of p21 in proliferative capacity in cancer cells. We found that CDKN1A is lowly expressed in BLCA, BRCA, COAD, KICH, LUAD, LUSC, PRAD, READ and STAD compared to normal samples, whereas it is highly expressed in CHOL, HNSC, KIRC, KIRP and THCA compared to normal cohorts. CDKN1A expression is significantly correlated with overall survival, disease-specific survival, disease-free survival and progression-free interval different cancer types. Additionally, CDKN1A is associated with CD4+ T cell, CD8+ T cell, Neutrophil, Macrophage and Myeloid dendritic cell infiltration in diverse cancer types. Functional experiments reveal that p21 overexpression leads to a significant reduction in proliferative capacity, facilitates cell apoptosis and senescence in multiple cancer cell lines. In contrast, silenced p21 facilitates cell growth and wound closure, prevent cell senescence in different cancer cell lines. In conclusion, our findings suggest that CDKN1A may serve as a valuable prognostic and immunotherapeutic marker in diverse cancer.

cancer biology↗

bioRxiv2024

Identifying Causal Relations between Gut Microbiome, Metabolic Dysfunction-Associated Fatty Liver Disease and the Novel Mediators of Blood Metabolites

BackgroundResearch has established connection between gut microbiome and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the causal relationships and the roles of potential mediating factors, such as blood metabolites, remain unclear. MethodsWe conducted a bidirectional and mediation Mendelian randomization (MR) study using the genome-wide summary statistics of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n =8,299), and the largest MAFLD GWAS data (1,483 cases and 17,781 controls). We used the inverse-variance weighted estimation method as our primary approach. The multivariable Mendelian randomization (MVMR) and two-step MR approaches were used to prioritize the most likely causal metabolites as mediators. Additionally, we conducted linkage disequilibrium score regression (LDSC) analyses to assess genetic correlations, and downstream gene-based analyses to investigate the shared biological mechanism. ResultsBy testing the causal effects of 205 bacterial pathways and 207 taxa on MAFLD, we identified 5 microbial taxa causally associated with MAFLD, notably the species Parabacteroides merdae (OR [95%CI] = 1.191[1.022-1.388], p = 0.025). Among 1,399 blood metabolites, 53 showed causal associations with MAFLD, with pregnenetriol sulfate identified as a mediator for genus Parabacteroides on MAFLD (proportion mediated = 16.30%). LDSC analysis also provided suggestive evidence for a potential genetic correlation between them (rg= 2.124, p=0.009). ConclusionsThe study suggested a novel causal relationship between gut microbial taxa and MAFLD, especially the genus Parabacteroides merdae and blood metabolite pregnenetriol sulfate might mediate this relationship. ImportanceOur study reveals novel insights into how the intersection of microorganisms living in the human gut, known as the gut microbiome, influences the development of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a condition increasingly recognized as a major global health concern. By identifying specific gut microbiome taxa and metabolites that contribute to the onset and progression of MAFLD, our findings enhance comprehension of this prevalent condition and unveil promising prospects for its prevention and intervention. We discovered that certain gut bacteria can affect the levels of blood metabolites, which in turn impact the livers health. This work carries significant implications for novel strategies for MAFLD prevention and treatment, including interventions aimed at modifying the gut microbiome. Our research underscores the gut-liver connection and its implications for metabolic diseases, contributing to future therapeutic developments that could improve public health worldwide. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/606637v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1b16347org.highwire.dtl.DTLVardef@ecf53eorg.highwire.dtl.DTLVardef@d8cb5borg.highwire.dtl.DTLVardef@10efe44_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Bridging tuning and invariance with equivariant neuronal representations

As we move through the world, we see the same visual scene from different perspectives. But how does the brain encode scene identity invariant to perspective, while remaining sensitive to these transformations? We propose a solution through equivariance, where perspective transformations induce structured changes in neuronal population responses. This framework implies a decomposition of population responses into orthogonal subspaces that are tuned and invariant. Testing our framework with large-scale neuronal recordings across four mouse visual cortical areas, we find that the equivariant structure is more pronounced in some higher-order areas (LM, AL) than in other areas (V1, RL). This equivariant structure accounts for the observed simultaneous increase in both population tuning and invariance. In comparison, early layers of an artificial neural network trained on image classification show similar structure, but later layers increase invariance at the cost of tuning. These results suggest equivariance is a principle to achieve flexible computations with neuronal populations.

neuroscience↗

bioRxiv2024

TrkA+ sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

cancer biology↗

bioRxiv2024

Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in MDS/AML

Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are hallmarks of HMA therapy. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identified TOPORS as a highly ranked loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of protein SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation or TOPORS demonstrates a favourable therapeutic index and is a rational treatment framework for High-Risk MDS (HR-MDS) or AML.

molecular biology↗

bioRxiv2024

Distinct streams for supervised and unsupervised learning in the visual cortex

Representation learning in neural networks may be implemented with supervised or unsupervised algorithms, distinguished by the availability of feedback. In sensory cortex, perceptual learning drives neural plasticity, but it is not known if this is due to supervised or unsupervised learning. Here we recorded populations of up to 90,000 neurons simultaneously from the primary visual cortex (V1) and higher visual areas (HVA), while mice learned multiple tasks as well as during unrewarded exposure to the same stimuli. Similar to previous studies, we found that neural changes in task mice were correlated with their behavioral learning. However, the neural changes were mostly replicated in mice with unrewarded exposure, suggesting that the changes were in fact due to unsupervised learning. The neural plasticity was concentrated in the medial HVAs and obeyed visual, rather than spatial, learning rules. In task mice only, we found a ramping reward prediction signal in anterior HVAs, potentially involved in supervised learning. Our neural results predict that unsupervised learning may accelerate subsequent task learning, a prediction which we validated with behavioral experiments.

neuroscience↗

bioRxiv2024

Proteomic comparison of epidemic Australian Bordetella pertussis biofilm cells

Bordetella pertussis causes whooping cough, a severe respiratory infectious disease. Studies have compared the currently dominant single nucleotide polymorphism (SNP) cluster I (pertussis toxin promoter allele, ptxP3) and previously dominant SNP cluster II (ptxP1) strains as planktonic cells. Since biofilm formation is linked with B. pertussis pathogenesis in vivo, this study compared the biofilm formation capabilities of representative strains of cluster I and cluster II. Confocal laser scanning microscopy found that the cluster I strain had a denser biofilm structure compared to the cluster II strain. Differences in protein expression of the biofilm cells were then compared using Tandem Mass Tagging (TMT) and high-resolution multiple reaction monitoring (MRM-hr). In total, 1453 proteins were identified of which 40 proteins had significant differential expression between the two strains in biofilm conditions. Of particular interest was a large increase in expression of energy metabolism proteins (cytochrome proteins PetABC and BP3650) in the cluster I strain. When the expression of these proteins was compared between 6 additional strains from each cluster, it was found that the protein expression varied between all strains. These findings suggest that there are large levels of individual proteomic diversity between B. pertussis strains in biofilm conditions despite the highly conserved genome of the species. Overall, this study revealed visual differences in biofilm structure between B. pertussis strains and highlighted strain specific variation in protein expression that dominate potential cluster specific changes that may be linked with the dominance of cluster I strains. ImportanceBordetella pertussis causes whooping cough. The currently circulating cluster I strains have taken over previously dominant cluster II strains. It is important to understand the reasons behind the evolution to develop new strategies against the pathogen. Recent studies have shown that B. pertussis can form biofilms during infection. This study compared the biofilm formation capabilities of a cluster I and a cluster II strain and identified visual differences in the biofilms. The protein expression between these strains grown in biofilms were compared and proteins identified with varied expression were measured with additional strains from each cluster. It was found that despite the highly conserved genetics of the species, there was varied protein expression between the additional strains. This study highlights that strain specific variation in protein expression during biofilm conditions that may dominate the cluster specific changes that may be linked to the dominance of cluster I strains.

microbiology↗

bioRxiv2023

Functional coherence of the Xist and RSX protein interactomes: X chromosome inactivation marsupials

Long range epigenetic silencing is epitomised by X chromosome inactivation (XCI) in mammals. It is mediated by independently evolved, non-homologous long noncoding RNAs in eutherian and marsupial mammals (XIST and RSX). The Xist interactome, comprising proteins that mediate the silencing process, is well documented in mouse studies. Here we interrogate proteins that interact with RSX using chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) in a marsupial representative, Monodelphis domestica. We identify 135 proteins that interact with RSX, of which 56 have orthologues in the Xist interactome. Remarkably, nearly 90% of the combined Xist and RSX interactomes are within the same protein-protein association network. This network clustered into three major groups with distinctive functional enrichments, including RNA splicing and processing, regulation of translation and ribosomal biogenesis, and epigenetic transcriptional silencing. The proteins of the RSX interactome were enriched for regions of intrinsic disorder in common with the Xist interactome, identifying this as a feature of ribonucleoprotein complexes associated with XCI. We also show that RNAi knockdown of representative RSX interactors, HNRNPK and CKAP4, led to reactivation of transcription from the inactive X chromosome, indicating a role for each in marsupial XCI. Thus, despite the absence of linear sequence homology between Xist and RSX, they exhibit extraordinary functional coherence that indicates potential for post-transcriptional regulation, a feature not previously associated with the molecular machinery of XCI.

genetics↗

bioRxiv2023

Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation

Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain size in vivo, reminiscent of the microcephaly phenotypes of patients. Together, our studies unveil a distinct molecular pathogenic mechanism from other known histone mutants, where H4K91 mutants misregulate cell fate during development through abnormal genomic localization.

molecular biology↗

bioRxiv2023

GeneCompass: Deciphering Universal Gene Regulatory Mechanisms with Knowledge-Informed Cross-Species Foundation Model

Deciphering the universal gene regulatory mechanisms in diverse organisms holds great potential to advance our knowledge of fundamental life process and facilitate research on clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms, resulting in limited collection and integration of complex features on various cell types across species. Recent breakthroughs in single-cell sequencing and advancements in deep learning techniques present an unprecedented opportunity to tackle this challenge. In this study, we developed GeneCompass, the first knowledge-informed, cross-species foundation model pre-trained on an extensive dataset of over 120 million single-cell transcriptomes from human and mouse. During pre-training, GeneCompass effectively integrates four types of biological prior knowledge to enhance the understanding of gene regulatory mechanisms in a self-supervised manner. Fine-tuning towards multiple downstream tasks, GeneCompass outperforms competing state-of-the-art models in multiple tasks on single species and unlocks new realms of cross-species biological investigation. Overall, GeneCompass marks a milestone in advancing knowledge of universal gene regulatory mechanisms and accelerating the discovery of key cell fate regulators and candidate targets for drug development.

bioinformatics↗

bioRxiv2023

NRF2 Regulates Contractile Vascular Smooth Muscle Cells Phenotypic Switching In Abdominal Aortic Aneurysm

OBJECTIVEEvidence from previous studies has demonstrated that NRF2 can protect cardiovascular progression,which prompted us to study if NRF2 is involved in AAA development. APPROACH AND RESULTSThe difference and function of NRF2 in AAA were verified on human aortic tissues combined with scRNA-seq samples.We then used angiotensin II (Ang II) infusion mouse model with VSMCs-specific knockout to study the role of NRF2 in AAA formation.Primary cultured VSMCs were used to study how NRF2 regulates contractile VSMCs phenotype.Patient specimens were obtained to investigate the relevance of NRF2 expression to human AAA disease. NRF2 was induced in abdominal aortic VSMCs in both mouse and human AAA tissues. VSMCs-specific NRF2 knockout increased experimental AAA formation. Mechanistically, NRF2 regulates the contractile VSMCs phenotypic through miRNA145, leading to increased classic contractile protein level to prevent the development of AAA. CONCLUSIONSNRF2 is a negative regulator of AAA development, and thus may represent a potentially new therapeutic target to inhibit AAA growth and rupture.

bioinformatics↗