PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast crosstalk and EndMT

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 17, 2025

Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects mechanisms of PD-1 inhibitor on collagen remodeling remain poorly understood. C57BL/6 mice were injected with anti-mouse antibody create inhibitor-treated model. function was measured by echocardiography, distribution analyzed Masson's trichrome staining Sirius Red staining. Single-nucleus RNA sequencing performed examine inhibition gene expression fibroblasts (CFs) endothelial cells (ECs). EC-CF crosstalk assessed using co-culture experiments ELISA. ChIP assay analyze regulation TCF12 TGF-β1 promoter. Western blot, qRT-PCR, immunofluorescence used detect TCF12, TGF-β1, endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels evaluated DHE staining, MDA content, SOD activity assays. We report newly discovered cardiotoxic effect inhibitor, which causes aberrant heart, marked decrease interstitial increase perivascular deposition. Mechanistically, does not directly affect CFs but instead impact them through crosstalk. reduces secretion ECs downregulating we identify as transcriptional promoter TGF-β1. This subsequently decreases CF activity, leading reduced Additionally, induces EndMT, The dysfunction induced results ROS accumulation ECs. Inhibiting N-acetylcysteine (NAC) preserves normal reversing downregulation EndMT Our suggest that ECs, imbalanced (decrease collagen) heart modulating TCF12/TGF-β1-mediated EndMT. NAC supplementation could be effective clinical strategy mitigate inhibitor-induced dysfunction.

Language: Английский

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Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure

Circulation Research, Journal Year: 2025, Volume and Issue: 136(7), P. 773 - 802

Published: March 27, 2025

Cardiac fibrosis, a hallmark of heart failure and various cardiomyopathies, represents complex pathological process that has long challenged therapeutic intervention. High-throughput omics technologies have begun revolutionizing our understanding the molecular mechanisms driving cardiac fibrosis are providing unprecedented insights into its heterogeneity progression. This review provides comprehensive analysis how techniques—encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics—are insight fibrosis. Genomic studies identified novel genetic variants regulatory networks associated with susceptibility progression, single-cell transcriptomics unveiled distinct fibroblast subpopulations unique signatures. Epigenomic profiling revealed dynamic chromatin modifications controlling activation states, proteomic analyses biomarkers potential targets. Metabolomic uncovered important alterations in energetics substrate utilization during fibrotic remodeling. The integration these multi-omic data sets led to identification previously unrecognized pathogenic targets, including cell-type-specific interventions metabolic modulators. We discuss advances development precision medicine approaches for while highlighting current challenges future directions translating effective strategies. systems-level perspective on may inform more effective, personalized related cardiovascular diseases.

Language: Английский

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C-C chemokine ligand 5 from subcutaneous adipose tissue has a central role in vascular aging

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

Published: March 31, 2025

Background: Aging is associated with adipose tissue alterations, oxidative stress, and fibrosis together the onset of cardiometabolic complications such as atherosclerosis. Although it has been shown that perivascular (PVAT) can participate to vascular damage, involvement subcutaneous (SCAT) - particularly through its secretory activity in aging remains poorly understood. We have previously human adipose-derived stromal cells (ASCs) from SCAT aged women display senescence stress. hypothesized ASC secretome contributes endothelial dysfunction, an early stage aging. Methods: Conditioned media were prepared ASCs isolated healthy young (<25y) or (>60y) women. The was analysed added on coronary artery (HCAEC). Using clinical cohorts, we evaluated expression C-C-chemokine-ligand-5 (CCL5)/Regulated upon Activation Normally T-expressed secreted (RANTES) individuals heart disease. Results: aged-donor induced cell dysfunction HCAEC, characterized by lower nitric oxide production, higher (greater p16 expression), a pro-adherent phenotype (elevated adhesion molecule secretion). Aged-donor also favored Endothelial-to-mesenchymal transition, characterised mesenchymal markers pro-migratory profile. showed CCL5/RANTES at level aged- vs. young-donor responsible for these effects. Accordingly, SCAT, but not epicardial tissue, blood pressure patients diseases, thus confirming important role disorders. Moreover, both HCAEC cohort receptor antagonist drug maraviroc prevented deleterious impact CCL5/RANTES. Conclusions: Our results highlighted ability released and, specifically, cells, induce which are steps potential link between phenomena hypertension particular.

Language: Английский

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Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression

Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)

Published: April 4, 2025

Abstract Background The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate progression. Plaque instability, the fundamental pathological factor acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights endothelial-to-mesenchymal transition (EndMT) exacerbates although link between FSH and EndMT has not been fully established. This investigation sought explore possible influence modulating EndMT. Methods In this study, apolipoprotein E -deficient ( ApoE −/− ) mice served as an model, while human umbilical endothelial cells (HUVECs) were used cellular models. Protein assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, nucleic acid–protein interactions evaluated using immunoprecipitation. m6A modification status determined by MeRIP, behaviors analyzed standard biochemical assays. Results indicate induces both vitro vivo. Additional suggested upregulates transcription Forkhead box protein M1 (FOXM1) at mRNA enhancing AlkB homolog 5, RNA demethylase (ALKBH5). reduces modifications on FOXM1 ALKBH5, leading increased nascent transcript stability . Dual-luciferase reporter assays highlighted cAMP-response element binding (CREB)’s essential function facilitating FSH-induced upregulation ALKBH5. Conclusions These suggest promotes ALKBH5 expression, facilitates N 6 -methyladenosine (m6A) demethylation , consequently, study elucidates impact instability provides insights into potential strategies prevent syndrome women. Graphical

Language: Английский

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Molecular mechanisms of endothelial–mesenchymal transition and its pathophysiological feature in cerebrovascular disease

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 19, 2025

Abstract The phenomenon of endothelial–mesenchymal transition (EndMT), a distinct subtype epithelial–mesenchymal (EMT), has garnered significant attention from scholars. EndMT refers to the process whereby endothelial cells (ECs) transform into mesenchymal in response various stimuli, resulting loss their original characteristics. This diverse implications both physiological and pathological states. Under conditions, plays crucial role development cardiovascular system. Conversely, under been identified as pivotal factor diseases. Nonetheless, comprehensive overview cerebrovascular disease is currently lacking. Here, we discuss heterogeneity occurrence regulatory factors involved its analyze feasibility therapeutic target, aiming provide solid theoretical foundation evidence address diseases caused by EndMT.

Language: Английский

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Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4265 - 4265

Published: April 30, 2025

Pulmonary hypertension (PH) is a serious cardiovascular disease caused by variety of pathogenic factors, which characterized increased pulmonary vascular resistance (PVR) and progressive elevation mean artery pressure (mPAP). This can lead to right ventricular hypertrophy and, in severe cases, heart failure even death. Vascular remodeling—a pathological modification involving aberrant vasoconstriction, cell proliferation, apoptosis resistance, inflammation the system—is significant hallmark PH critical process its progression. Recent studies have found that remodeling involves participation diversity cellular alterations, such as dysfunction endothelial cells (PAECs), proliferation migration smooth muscle (PASMCs), phenotypic differentiation fibroblasts, inflammatory response immune cells, pericyte proliferation. review focuses on mechanisms intercellular crosstalk these process, emphasizing recent advances knowledge regarding signaling pathways, responses, apoptosis, To develop better treatments, list possible therapeutic approaches meant slow down certain biological functions provided, with aim providing new insights into treatment simplifying intricacies complex connections. In this review, comprehensive academic databases PubMed, Embase, Web Science, Google Scholar were systematically searched discuss relevant human animal PH, focus PH.

Language: Английский

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Tectorigenin protects against cardiac fibrosis in diabetic mice heart via activating the adiponectin receptor 1-mediated AMPK pathway

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116589 - 116589

Published: April 17, 2024

Diabetic cardiomyopathy (DCM) is a common severe complication of diabetes that occurs independently hypertension, coronary artery disease, and valvular cardiomyopathy, eventually leading to heart failure. Previous studies have reported Tectorigenin (TEC) possesses extensive anti-inflammatory anti-oxidative stress properties. In this present study, the impact TEC on diabetic was examined. The model DCM in mice established with combination high-fat diet STZ treatment. Remarkably, treatment significantly attenuated cardiac fibrosis improved dysfunction. Concurrently, also found mitigate hyperglycemia hyperlipidemia mouse. At molecular level, involved activation AMPK, both vitro vivo, by enhancing its phosphorylation. This achieved through regulation endothelial-mesenchymal transition via AMPK/TGFβ/Smad3 pathway. Furthermore, it demonstrated level ubiquitination adiponectin receptor 1 (AdipoR1) protein associated TEC-mediated improvement dysfunction mice. Notably substantial reduction myocardial fibrosis. conclusion, improves modulating AdipoR1/AMPK signaling These findings suggest could be an effective therapeutic agent for cardiomyopathy.

Language: Английский

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Extracellular Vesicles Derived from Type 2 Diabetic Mesenchymal Stem Cells Induce Endothelial Mesenchymal Transition under High Glucose Conditions via the TGFb/Smad2-3 Signaling Pathway

Stem Cells and Development, Journal Year: 2024, Volume and Issue: 33(11-12), P. 262 - 275

Published: May 8, 2024

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which results in delayed wound healing. Mesenchymal stem cells (MSC) play a vital role supporting (EC) and promoting healing via paracrine effects through their secretome-containing extracellular vesicles. We previously reported the impaired ability of adipose tissue-derived MSC from T2DM donors; however, whether vesicles isolated (dEV) exhibit altered functions comparison to those derived healthy donors (nEV) still unclear. In present study, we found that nEV induced EC survival angiogenesis, whereas dEV lost these abilities. addition, under high glucose conditions, protected mesenchymal transition (EndMT), significantly EndMT by activating TGF/Smad3 signaling pathway, tube formation vivo abilities EC. Interestingly, treatment dEV-internalized rescued effects. Of note, internalization into T2DM-derived tissue-MSC resulted production an n-dEV, inhibited supported db/db mice severe wounds. Taken together, our findings suggest dysfunction promotion EndMT. Moreover, can be considered as promising candidate for cell-free therapy protect T2DM.

Language: Английский

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Targeting fibroblast phenotype switching in cardiac remodelling as a promising antifibrotic strategy

European Heart Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Abstract Myocardial fibrosis, a common feature of heart disease, remains an unsolved clinical challenge. Fibrosis resolution requires activation cardiac fibroblasts exhibiting context-dependent beneficial and detrimental dichotomy. Here, we explored the hypothesis fibroblast reversible transition between quiescence activated myofibroblastic states as manifestation cell phenotypic switching in myocardial remodelling. In support, gene regulatory networks executing conversion to myofibroblasts vice versa fibrosis are reconstructed using TRANSPATH database. scenario triggered by transforming growth factor β, cardinal mediator tissue signalling cascades governing entry into or exit from specific statures fibrotic remodelling were dissected. It is suggested that constitutes central gait toward guiding state-gating strategies counteract adverse devastating disorder with no approved therapeutic option.

Language: Английский

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The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

Aging is a major risk factor for cardiovascular diseases (CVD), and mitochondrial autophagy impairment considered significant physiological change associated with aging. Endothelial cells play crucial role in maintaining vascular homeostasis function, participating various processes such as regulating tone, coagulation, angiogenesis, inflammatory responses. As aging progresses, endothelial worsens, leading to the development of numerous diseases. Therefore, vital preventing treating age-related However, there currently lack systematic reviews this area. To address gap, we have written review provide new research therapeutic strategies managing

Language: Английский

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