Acute Severe Hypoxia Decreases Mitochondrial Chain Complex II Respiration in Human Peripheral Blood Mononuclear Cells

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 705 - 705

Published: Jan. 15, 2025

Peripheral blood mononuclear cells' (PBMCs) mitochondrial respiration is impaired and likely involved in myocardial injury heart failure pathophysiology, but its response to acute severe hypoxia, often associated with such diseases, largely unknown humans. We therefore determined the effects of hypoxia on PBMC ROS production healthy volunteers exposed controlled oxygen reduction, achieving an inspired fraction 10.5%. also investigated potential relationships gene expression key biomarkers succinate inflammation, as inflammation share common mechanisms cardiovascular disease. Unlike global respiration, hypoxemia a spO2 ≤ 80% significantly reduced complex II (from 6.5 ± 1.2 3.1 0.5 pmol/s/106 cell, p = 0.04). Complex activity correlated positively (r 0.63, 0.02) inversely receptor SUCNR1 -0.68), alpha-subunit hypoxia-inducible factor (HIF-1α, r -0.61), chemokine ligand-9 -0.68) interferon-stimulated 15 -0.75). In conclusion, specifically impairs association succinate, HIF-1α pathway interactions human PBMCs. These results support further studies investigating whether modulation might modify inflammatory metabolic alterations observed failure.

Language: Английский

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Activation of the cGAS-STING pathway mediated by Irgm1 contributes to the development of restrictive cardiomyopathy induced by cTnIR193H mutation

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

Published: April 4, 2025

Restrictive cardiomyopathy (RCM) is a rare, fatal disorder that rapidly progresses in children. TNNI3 mutations represent the most common genetic cause. Although cTnI are known to increase myofilament calcium sensitivity and impair diastolic function, this mechanism alone does not fully account for disease pathogenesis. Recent studies have revealed immune system plays an important role cardiovascular diseases, however, its involvement RCM remains unclear. Here, we generated classic cTnIR193H mouse model using CRISPR/Cas9. Cardiac RNA-seq analysis indicated marked activation of innate pathways. moreover, biotin-mediated proximity labeling combined with quantitative mass spectrometry identified differential interactors mutant, Irgm1 emerging as significantly altered immune-related protein. Notably, mutation enhances binding without affecting expression, thereby indirectly inhibiting normal function. This aberrant interaction activates cGAS-STING pathway elicits type I interferon response hearts mice. Furthermore, treatment STING inhibitor C176 partially restored function alleviated cardiac fibrosis. Taken together, study reveals first time mechanisms play crucial pathogenesis provides potential therapeutic target from immunological perspective.

Language: Английский

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Designing multicellular cardiac tissue engineering technologies for clinical translation

Seminars in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 171, P. 103612 - 103612

Published: April 29, 2025

Cardiovascular diseases remain the leading cause of death worldwide-claiming one-third all deaths every year. Current two-dimensional in vitro cell culture systems and animal models cannot completely recapitulate clinical complexity these humans. Therefore, there is a dire need for higher fidelity biological capable replicating phenotypes to inform outcomes therapeutic development. Cardiac tissue engineering (CTE) strategies have emerged fulfill this by design three-dimensional myocardial from human pluripotent stem cells. In way, CTE serve as highly controllable variety applications-including physiological pathological modeling, drug discovery preclinical testing platforms, even direct interventions clinic. Although significant progress has been made development technologies, critical challenges necessary refinements are required derive more advanced heart technologies. review, we distill three focus areas field address: I) Generating cardiac muscle types scalable manufacturing methods, II) Engineering structure, function, analyses, III) Curating system specific application. each our areas, emphasize importance designing mimicking intricate intercellular connectivity discuss fundamental considerations that subsequently arise. We conclude highlighting cutting-edge applications use technologies modeling repair damaged diseased hearts.

Language: Английский

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Atherosclerosis and inflammation – from pathogenesis to treatment: current state of affairs (Part I)

Bulletin of Siberian Medicine, Journal Year: 2025, Volume and Issue: 24(1), P. 141 - 153

Published: April 16, 2025

Atherosclerosis and atherosclerosis-related cardiovascular diseases are a significant public health concern rapidly evolving area of research in both fundamental clinical medicine. Despite the extensive history studying, many aspects atherosclerosis etiology pathogenesis remain unclear. Traditionally, has been viewed terms localized accumulation specific lipoprotein fractions arterial wall. However, innate adaptive immunity play active roles atherogenesis. Cells mediators immune system engage intricate interactions with cellular extracellular components all layers vascular For this reason, scientific community have reached consensus on crucial role inflammation onset, progression, destabilization an atherosclerotic plaque. Therefore, atherogenesis can be considered not only as metabolic disorder, but also immunoinflammatory process. The aim lecture was to summarize contemporary data regarding at various stages continuum.

Language: Английский

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Immune Dysregulation in the Oral Cavity during Early SARS-CoV-2 Infection

Journal of Dental Research, Journal Year: 2024, Volume and Issue: 103(12), P. 1258 - 1270

Published: Oct. 12, 2024

Tissue-specific immune responses are critical determinants of health-maintaining homeostasis and disease-related dysbiosis. In the context COVID-19, oral reflect local host-pathogen dynamics near site infection serve as important “windows to body,” reflecting systemic invading SARS-CoV-2 virus. This study leveraged multiplex technology characterize salivary SARS-CoV-2–specific immunological landscape (37 cytokines/chemokines 11 antibodies) during early infection. Cytokine/immune profiling was performed on unstimulated cleared whole saliva collected from 227 adult SARS-CoV-2+ participants 37 controls. Statistical analysis modeling revealed significant differential abundance 25 cytokines (16 downregulated, 9 upregulated). Pathway demonstrated is associated with suppression type I/III interferon blunted natural killer–/T-cell responses, a potential novel immune-evasion strategy enabling virus-associated occurred concomitantly upregulation proinflammatory pathways including marked increases in acute phase proteins pentraxin-3 chitinase-3-like-1. Irrespective infection, prior vaccination increased total α-SARS-CoV-2-spike (trimer), -S1 protein, -RBD, -nucleocapsid antibodies, highlighting importance COVID-19 eliciting mucosal responses. Altogether, our findings highlight stable accessible biofluid for monitoring host over time suggest that oral-mucosal dysregulation hallmark possible implications viral evasion mechanisms.

Language: Английский

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The Hepatocyte Growth Factor/Cmet Axis in Autoimmune Cardiac Inflammation and Beyond

Published: Jan. 1, 2024

Myocarditis is a potentially life-threatening disorder that challenging to diagnose and treat. T cell-mediated autoimmunity now recognized as key mechanism in myocarditis. Under physiologic conditions, regulatory cells maintain peripheral tolerance prevent spontaneous myocarditis development, but damaged tissue activation of the innate immune system promotes effector cell expansion progression. Our lab has previously identified subset memory characterised by expression hepatocyte growth factor (HGF) receptor, cMet, selectively localise inflamed cardiac muscle. Further studies have implicated cMet+ mediators acute T- mediated autoimmune myocarditis, also being central development murine chronic ultimately, dilated cardiomyopathy (DCM). However, HGF been shown exert multiple complex effects on inflammation its resolution.Here, we review which mediate cMet modulation responses heart.

Language: Английский

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Distinct circulating cytokine levels in patients with angiography-proven coronary artery disease compared to disease-free controls

International Journal of Cardiology Cardiovascular Risk and Prevention, Journal Year: 2024, Volume and Issue: 22, P. 200307 - 200307

Published: July 4, 2024

Systemic inflammation has a critical role in the development of symptomatic coronary artery disease (CAD). Identification inflammatory pathways may provide platform for novel therapeutic approaches. We sought to determine whether there are differences circulating cytokine profiles between patients with CAD and disease-free controls as well according severity disease.

Language: Английский

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FBXL19 in Endothelial Cells Protects the Heart from Influenza A Infection by Enhancing Antiviral Immunity and Reducing Cellular Senescence Programs

AJP Heart and Circulatory Physiology, Journal Year: 2024, Volume and Issue: 327(4), P. H937 - H946

Published: Aug. 16, 2024

Influenza A virus (IAV) infection while primarily affecting the lungs, is often associated with cardiovascular complications. However, mechanisms underlying this association are not fully understood. Here, we investigated potential role of FBXL19, a member Skp1-Cullin-1-F-box family E3 ubiquitin ligase, in IAV-induced cardiac inflammation. We demonstrated that FBXL19 overexpression endothelial cells (ECs) reduced viral titers and IAV matrix protein 1 (M1) levels increasing antiviral gene expression, including interferon (IFN)-α, -β, -γ RANTES (regulated on activation normal T cell expressed secreted) tissue IAV-infected mice. Moreover, EC-specific attenuated infection-reduced regulatory factor 3 (IRF3) level without altering its mRNA suppressed Furthermore, triggered cellular senescence programs heart as indicated by upregulation p16 p21 downregulation lamin-B1 levels, which were partially reversed ECs. Our findings indicate protects against damage enhancing interferon-mediated signaling, reducing inflammation, suppressing programs.

Language: Английский

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Exosomes derived from microRNA-540-3p overexpressing mesenchymal stem cells promote immune tolerance via the CD74/nuclear factor-kappaB pathway in cardiac allograft

World Journal of Stem Cells, Journal Year: 2024, Volume and Issue: 16(12), P. 1022 - 1046

Published: Dec. 12, 2024

BACKGROUND Heart transplantation is a crucial intervention for severe heart failure, yet the challenge of organ rejection significant. Bone marrow mesenchymal stem cells (BMSCs) and their exosomes have demonstrated potential in modulating T cells, dendtitic (DCs), cytokines to achieve immunomodulatory effects. DCs, as key antigen-presenting play critical role shaping immune responses by influencing T-cell activation cytokine production. Through this modulation, BMSCs enhance graft tolerance prolonging survival. AIM To explore effects derived from overexpressing microRNA-540-3p (miR-540-3p) on cardiac allograft tolerance, focusing how these DCs activity through CD74/nuclear factor-kappaB (NF-κB) pathway. METHODS Rat models were used assess impact miR-540-3p-enhanced allografts. MiR-540-3p expression was manipulated BMSCs, collected administered rat post-heart transplantation. The study monitored levels major histocompatibility complex II, CD80, CD86, CD274 quantified CD4+ CD8+ regulatory profiles. RESULTS Exosomes miR-540-3p-overexpressing lead reduced markers CD74 NF-κB p65 cells. Rats treated with showed decreased inflammation improved function, indicated lower pro-inflammatory (interleukin-1β, interferon-γ) higher anti-inflammatory (interleukin-10, transforming growth factor β1). Additionally, miR-540-3p skewed profiles towards increasing ratio shifting secretion favor acceptance. CONCLUSION significantly prolong survival CD74/NF-κB pathway, which regulates activities These findings highlight promising therapeutic strategy improve outcomes potentially reduce need prolonged immunosuppression.

Language: Английский

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Heart Failure Is Closely Associated With the Expression Characteristics of Type I Interferon‐Related Genes

Clinical Cardiology, Journal Year: 2024, Volume and Issue: 48(1)

Published: Dec. 20, 2024

The association between the expression of type I interferon related genes (TIIRGs) and EFrHF is not well understood. This study aimed to investigate correlation patterns TIIRGs using bioinformatics analysis.

Language: Английский

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