T cells in cardiac health and disease

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(2)

Published: Jan. 15, 2025

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. T lymphocytes are crucial components adaptive immune system that have emerged as key mediators both cardiac health development progression CVD. This Review explores diverse roles cell subsets, including Th1, Th17, γδ cells, Tregs, myocardial inflammatory processes such autoimmune myocarditis infarction. We discuss contribution cells to injury remodeling, emphasis on specific receptors, e.g., CD69, critical regulating tolerance maintaining balance between subsets heart. Additionally, we offer perspective recent advances cell-targeted therapies their potential modulate responses improve clinical outcomes patients CVD heart transplant recipients. Understanding intricate interplay cardiovascular pathology is essential for developing novel immunotherapeutic strategies against

Language: Английский

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Antigen Presentation by Graft Myofibroblasts Leads to Murine Heart Transplantation Rejection through the Autophagy Signaling Pathway

Published: Jan. 29, 2025

Background Fibrobalst plays a critical role in heart physiology and pathology, yet their immunological transplanted grafts remains unclear, particularly the mechanisms involved. Methods Heart transplantation was performed mouse models (C57BL/6J, BALB/c, Postn^MCM, Rosa26-tdTomato, ATG5^floxp/floxp). Single-cell RNA sequencing, qPCR, western blotting, flow cytometry, immunofluorescence staining were used to identify fibroblast subpopulations assess functions.In vivo vitro assays explored of MHC molecule expression. Results Using scRNA-seq, staining, we identified three distinct cardiac grafts, including silent fibroblasts, myofibroblasts, MHC^high fibroblasts. Activation expression fibroblasts found be dependent on IFN-γ both vitro.Genetic lineage tracing revealed that myofibroblasts exhibit higher class I expression, which appears mediated by periostin (Postn). Differential gene analysis between indicated upregulation autophagy signaling pathway. Furthermore, diminished observed ATG5-deficient vitro. Conditional deletion ATG5 using Cre/floxp system led prolonged graft survival, reduced infiltration inflammatory cytokines as well chemokines, decreased CD8 + T cell proliferation. Conclusion This study suggests enhance antigen presentation via during transplantation. These findings give valuable insights into underlying therapeutic targets for survival.

Language: Английский

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IFNγ activates an immune-like regulatory network in the cardiac vascular endothelium

Journal of Molecular and Cellular Cardiology Plus, Journal Year: 2025, Volume and Issue: 11, P. 100289 - 100289

Published: Feb. 19, 2025

The regulatory mechanisms underlying the response to pro-inflammatory cytokines in cardiac diseases are poorly understood. Here, we use iPSC-derived cardiovascular progenitor cells (CVPCs) model interferon gamma (IFNγ) human tissue. We generate RNA-seq and ATAC-seq for four CVPCs that were treated with IFNγ compare them paired untreated controls. Transcriptional differences after treatment show initiates an innate immune cell-like response, shifts CVPC transcriptome toward coronary artery aorta profiles, stimulates expression of endothelial cell-specific genes. Analysis accessible chromatin shows is a potent remodeler establishes IRF-STAT immune-cell like network. Finally, 11 GWAS risk variants 8 common overlap IFNγ-upregulated peaks. Our findings reveal insights into IFNγ-induced activation immune-like network tissue potential role elements this pathway play diseases.

Language: Английский

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Transcriptional Atlas of Cardiac Disease

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Cardiovascular diseases (CVD), including of the cardiac muscle (cardiac disease), account for a substantial proportion global morbidity and mortality. Although there are several life-saving drugs devices that have improved prognosis, improvement in last decade has stabilized, largely because no or very few targeted treatments combat against CVD. In search better understanding CVD new therapeutic targets, basic mechanistic studies warranted. One important tool is use single-cell single-nucleus RNA sequencing (snRNAseq) approaches. Several individual specific phenotypes been studied this way, but efforts to pool all data into one comprehensive dataset lacking. We created first human disease reference atlas so far, encompassing snRNAseq from 7 datasets, spanning 8 different (n=117) healthy tissues (n=37), with over 1.6 million nuclei. This database integrated datasets tissue patients atrial fibrillation (AF), acute myocarditis (AM), ischemic heart (IHD), myocardial infarction (MI), ACM (arrhythmogenic cardiomyopathy), DCM (dilated HCM (hypertrophic cardiomyopathy) NCM (noncompaction cardiomyopathy). revealed transcriptional disparities dividing acquired (genetic) cardiomyopathies, which was supported by pathway analyses based on differentially expressed genes. Hallmarks were dysregulated cellular communication motility processes, strong proof fibroblast as central mediator. Cardiomyopathies other hand accompanied processes involved contractile function heart, high contribution cardiomyocytes. Employing novel explore if repurposing may be useful, it prime targets fibroblasts (ENO2) cardiomyocytes (HTR5A) exist. summary, represents an step research recapitulating various distinct presenting way gaining insights multiple simultaneously.

Language: Английский

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Sarcomeric Remodelling in Human Heart Failure unraveled by single molecule long read sequencing

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Dysregulation of alternative splicing – mediated by factors such as RBM20 or SLM2 can affect proper gene isoform control disrupts homeostasis and underpins severe cardiomyopathy in both animal models patients. Although innovative therapies target various sarcomeric components, the impact switching cardiac disease remains poorly understood. Here, we applied nanopore long-read sequencing to map full-length transcriptome left ventricular tissue from thirteen nonfailing controls, ten patients with dilated (DCM), ischemic (ICM). Our analysis identified 78,520 transcripts, 31% which represent novel isoforms known genes. Notably, transcriptomes DCM ICM were largely indistinguishable, indicating that end-stage heart failure is characterized a convergent landscape, irrespective etiology. Among 11 prototypical sarcomere genes, 10 displayed highly significant shifts (p= 5.23×10 −45 2.89×10 −200 ). Focusing on tropomyosin, observed while predominant TPM1 showed moderate up-regulation its transcript isoforms, transcripts derived TPM3 —typically expressed at lower levels healthy heart—were markedly increased failure.

Language: Английский

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Interface Between Cardioimmunology, Myocardial Health, and Disease: A Compendium

Circulation Research, Journal Year: 2024, Volume and Issue: 134(12), P. 1661 - 1662

Published: June 6, 2024

Language: Английский

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Cardiac Fibroblasts: Answering the Call

AJP Heart and Circulatory Physiology, Journal Year: 2024, Volume and Issue: 327(3), P. H681 - H686

Published: Aug. 2, 2024

Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network contributing essential physiological processes. In response injury such as myocardial infarction or pressure overload, become activated, leading increased ECM production that can ultimately drive left ventricular remodeling progress failure. Recently,

Language: Английский

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