Biology subjects

Luxan, G.

Publications and source records attributed to Luxan, G..

8 recordsLinked to original sources

bioRxiv2025

Haematopoietic loss of KDM6A impairs cardiac recovery in heartfailure via epigenetic reprogramming of myeloid cells

Clonal haematopoiesis (CH) is recognized as a potent independent risk factor for cardiovascular disease (CVD). While mutations in common CH-associated genes, such as DNMT3A and TET2, have been extensively studied, the pathological roles of other CH mutations remain poorly understood. Among these is KDM6A (UTX), an X-linked histone demethylase recently found to be commonly mutated in patients with heart failure. The mechanistic implications of KDM6A mutations in cardiac dysfunction remain largely unknown. Here, using multi-omics profiling and functional characterisation of murine models and patient-derived data, we demonstrate that haematopoietic loss of KDM6A substantially impairs cardiac recovery following myocardial infarction (MI). KDM6A deficiency enhances systemic and cardiac inflammation, characterized by augmented myeloid cell infiltration into the infarcted murine heart. Single-cell chromatin accessibility and single-cell RNA sequencing analyses revealed profound epigenetic and transcriptional reprogramming in KDM6A-deficient myeloid cells, notably CCR2 recruited macrophages and neutrophils. These cells exhibited heightened inflammatory (Il1b, Nlpr3, Saa3) and chemotactic signatures (Ccr2, Mif, Cxcl12), increased activation of inflammatory transcription factor networks (AP-1, C/EBP), disrupted chromatin architecture, and enhanced glycolytic activity. Clinically, patients with heart failure harbouring KDM6A-driven CH exhibited increased pro-inflammatory monocyte signatures (CCR2, NLPR3, NFKB1, FOS, JUN, IL6R, IL32), underscoring the translational relevance. Integrative analyses further predicted pathogenic crosstalk between KDM6A-mutated monocytes and cardiac resident cells and was experimentally validated by demonstrating that KDM6A-silenced macrophages drive cardiomyocyte hypertrophy and cardiac fibroblast activation. Our findings establish a critical mechanistic link between KDM6A-driven CH, immune dysregulation, and worsened cardiac outcomes post-MI, highlighting novel avenues for personalized therapeutic strategies in heart failure.

cell biology↗

bioRxiv2025

Endothelial decorin is increased by ageing and, induces inflammation and diastolic dysfunction in the heart

AimsCardiovascular disease is the leading cause of death in the European Union and aging is one of its major risk factors resulting in the progressive deterioration of the cardiac structures and function. Here, we have combined single-nucleus-RNA-sequencing, imaging, and molecular and cell biology approaches to explore the maladaptive signals that drive cardiac ageing. Methods and resultsSingle-nucleus-RNA-sequencing analysis of young (3 months) and old (18 months) murine hearts revealed that the expression of decorin, a secreted proteoglycan expressed in the extracellular matrix of endothelial cells, is induced by ageing. Decorin treatment via osmotic mini-pump induced diastolic dysfunction and a pro-inflammatory environment in the myocardium characterized by increased infiltration of immune cells, increased expression of IL- 1{beta} in endothelial cells and microvascular leakage in 3 months old mice. In vitro, decorin treatment induces cardiomyocyte hypertrophy, the expression of different pro-inflammatory cytokines like IL1B in endothelial cells, and compromises the endothelial barrier function. ConclusionsTogether, our results identify decorin as a novel player contributing to cardiac aging and disease. Decorin contributes to the age-related structural and functional dysfunction of the heart by inducing a pro-inflammatory environment in the myocardial microvasculature, a hallmark of cardiac ageing. Translational perspectiveAgeing is a major risk factor of cardiovascular disease and the molecular and cellular mechanisms that drive this process have not been completely described. The data presented here identifies decorin as a novel player contributing to systemic inflammation and microvascular dysfunction, two hallmarks of ageing. Although, because of its role regulating TGF-{beta} signalling, decorin has been proposed for anti-fibrotic therapies, the pro-inflammatory effects observed on the cardiac microvasculature should be taken into account for the employment of decorin as an antifibrotic agent to treat disease associated cardiac fibrosis.

physiology↗

bioRxiv2025

STAT3 expression is reduced in cardiac pericytes in HFpEF and its loss reduces cellular adhesion and induces pericyte senescence

Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure cases and is characterised by reduced pericyte coverage. While the contributions of other cardiac cell types to HFpEF are well-studied, the role of pericytes remains less understood. Using murine single-nucleus RNA sequencing to study cardiac pericytes in HFpEF, we identified reduced STAT3 expression as a hallmark of HFpEF pericytes. Mechanistic studies in vitro revealed that STAT3 deletion induces cellular senescence and impairs pericyte adhesion, recapitulating HFpEF-like characteristics. These findings suggest that STAT3 is crucial for maintaining pericyte homeostasis and highlight its reduction as a potential driver of pericyte loss, a defining feature of HFpEF.

cell biology↗

bioRxiv2023

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

BackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown. MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts. ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression of Rgs5 was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g. TGFB2 and PDGFB. Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of smooth muscle actin in a TGF{beta}2-dependent mechanism. ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

physiology↗

bioRxiv2023

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/521766v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10a365aorg.highwire.dtl.DTLVardef@176807borg.highwire.dtl.DTLVardef@ed3f47org.highwire.dtl.DTLVardef@1d572b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Ageing impairs the neuro-vascular interface in the heart

Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well1. It is known that nerves align with vessels during development2, but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability.

physiology↗

bioRxiv2020

SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

BackgroundThe coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality in COVID-19 patients. It is unclear whether cardiac injury may have been caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here we investigate whether human cardiomyocytes are permissive for SARS-CoV-2 infection. MethodsInfection was induced by two strains of SARS-CoV-2 (FFM1 and FFM2) in human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CM) and in two models of human cardiac tissue. ResultsWe show that SARS-CoV-2 infects hiPS-CM as demonstrated by detection of intracellular double strand viral RNA and viral spike glycoprotein protein expression. Increasing concentrations of virus RNA are detected in supernatants of infected cardiomyocytes, which induced infections in CaCo-2 cell lines documenting productive infections. SARS-COV-2 infection induced cytotoxic and pro-apoptotic effects and abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a iPS-derived human 3D cardiosphere tissue models. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. ConclusionsThe demonstration that cardiomyocytes are permissive for SARS-CoV-2 infection in vitro warrants the further in depth monitoring of cardiotoxic effects in COVID-19 patients. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study demonstrates that human cardiac myocytes are permissive for SARS-CoV-2 infection. C_LIO_LIThe study documents that SARS-CoV-2 undergoes a full replicatory circle and induces a cytotoxic response in cardiomyocytes. C_LIO_LIInfection was confirmed in two cardiac tissue models, including living human heart slices. C_LI What are the Clinical Implications?O_LIThe study may provide a rational to explain part of the cardiotoxicity observed in COVID-19 patients C_LIO_LIThe demonstration of direct cardiotoxicity induced by SARS-CoV-2 warrants an in depth further analysis of cardiac tissue of COVID-19 patients and a close monitoring for putative direct cardiomyocyte injury. C_LIO_LIThe established models can be used to test novel therapeutic approaches targeting COVID-19. C_LI

cell biology↗

bioRxiv2020

Effects of Post-Myocardial Infarction Heart Failure on the Bone Vascular Niche

Bone vasculature provides protection and signals necessary to control stem cell quiescence and renewal1. Specifically, type H capillaries, which highly express Endomucin, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells2-4. The age-dependent decline in type H endothelial cells was shown to be associated with bone dysregulation and accumulation of hematopoietic stem cells, which display cell-intrinsic alterations and reduced functionality3. The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Inhibition of NLRP3-dependent IL-1{beta} production partially prevents the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.

cell biology↗