Biology subjects

Sassi, Y.

Publications and source records attributed to Sassi, Y..

7 recordsLinked to original sources

bioRxiv2026

Targeting IL-6-STAT3/STAT4 Signaling Restores FOXP3 Expression in Pulmonary Arterial Endothelium and Reveals Novel Biomarkers for PAH

BackgroundInterleukin-6 (IL-6) is a central driver of pulmonary vascular remodeling in idiopathic, heritable, and connective tissue disease-associated pulmonary arterial hypertension (PAH). Elevated IL-6 correlates with right ventricular (RV) dysfunction and poor survival. However, the specific downstream mechanisms by which IL-6 drives pathogenesis remain poorly defined. We investigated the therapeutic impact of direct IL-6 neutralization and its regulation of a novel epigenetic signaling axis in PAH. Materials and MethodsWe evaluated species-specific IL-6-neutralizing antibodies in murine Sugen/hypoxia and rat monocrotaline models of PAH. RV structure and function were assessed using cardiac MRI and invasive hemodynamics. Lung transcriptomic profiling was performed by RNA sequencing mouse lung tissue. Key findings were validated in explanted human PAH lungs, serum, and peripheral blood mononuclear cells (PBMCs), and further interrogated through mechanistic in vitro studies in human pulmonary artery endothelial cells (PAECs). ResultsIL-6 neutralization significantly improved RV function, reduced pulmonary arterial pressures, and attenuated pulmonary vascular remodeling in both experimental models. Transcriptomic analysis identified a dysregulated FOXP3 signaling axis. Mechanistically, IL-6 induced cooperative binding of phosphorylated STAT3 and STAT4 to the FOXP3 promoter, facilitating DNMT1-mediated DNA methylation and stable gene silencing. IL-6 blockade restored downstream FOXP3 expression, rescued downstream BMPR2 signaling, and re-established endothelial homeostasis. In clinical PAH cohorts, FOXP3 expression was markedly reduced and inversely correlated with circulating IL-6 levels and indices of disease severity. ConclusionIL-6 drives pulmonary hypertension through STAT3/STAT4- and DNMT1-dependent epigenetic repression of FOXP3, linking chronic inflammation to BMPR2 dysfunction and pulmonary vascular remodeling. IL-6 neutralization reverses this pathogenic program in experimental PAH. FOXP3 emerges as a mechanistic biomarker of disease severity and a potential tool for precision stratification of patients likely to benefit from IL-6-targeted therapies. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LISynergistic Gene Repression: The study demonstrates that phosphorylated STAT3 functional transcriptional complex that binds directly to the FOXP3 promoter. Acting as a molecular scaffold, this complex actively represses FOXP3 expression within the pulmonary endothelium. C_LIO_LIEpigenetic Silencing Mechanism: IL-6 does not merely induce a transient suppression of FOXP3. Instead, IL-6/STAT3 signaling recruits DNMT1 to the FOXP3 promoter, leading to site-specific DNA methylation and long-term epigenetic silencing. This mechanism provides a direct molecular link between chronic systemic inflammation and sustained pulmonary vascular injury. C_LIO_LIThe FOXP3-BMPR2 Connection: The findings identify FOXP3 as a critical positive regulator of BMPR2 expression. Neutralization of IL-6 disrupts this pathological inhibitory loop, permitting restoration of BMPR2 signaling, the central gatekeeper of pulmonary vascular integrity and homeostasis. C_LIO_LITranslational Biomarkers: Importantly, the molecular changes within the lung are reflected systemically. Suppressed FOXP3 expression is readily detectable in PBMCs and serum, offering a non-invasive biomarker that correlates with pulmonary hemodynamic status and vascular health. C_LI Clinical ImplicationsO_LIPrecision Patient Stratification: FOXP3 expression in PBMCs and serum functions as a surrogate marker of pulmonary vascular epigenetic health. This could identify a specific inflammatory endotype of PAH patients most likely to respond to IL-6-targeted therapies. C_LIO_LIPrognostic Biomarker: Because FOXP3 levels integrate both systemic inflammatory burden and dysfunction of the RV-pulmonary vascular axis, they may provide a more sensitive tool for monitoring therapeutic response and predicting clinical worsening than current standard-of-care markers. C_LI

molecular biology↗

bioRxiv2025

Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension

BackgroundPulmonary Arterial Hypertension (PAH) is a devastating cardiopulmonary disease characterized by pulmonary vascular remodeling due to vascular cells dysfunction. Among other clinical signs, emerging data suggest poor sleep quality in patients with PAH; however, how poor sleep impacts hemodynamic burden, symptom severity, and pulmonary vascular remodeling during PAH progression remains unknown. MethodsWe used two models of sleep disturbances (sleep fragmentation and chronic jet lag) and different mouse models of PAH to determine the effects of poor sleep on PAH. We carried out timepoint quantitative RT-PCR analyses to define the clock gene oscillations in human pulmonary artery smooth muscle cells (PASMCs) isolated from non-PAH and PAH patients. Bulk RNA-sequencing analysis, immunostaining, and proliferation assays were used to explore the mechanisms by which poor sleep impacts PAH. Electroencephalogram and Electromyogram recordings (EEG/EMG) were used to determine whether PAH affects sleep in mice. ResultsPoor sleep exacerbated right ventricular dysfunction, pulmonary vascular remodeling, and PAH. RNA-seq and immunostaining analyses showed that poor sleep induces lung inflammation. Inflammation affected the pulmonary vascular molecular clock to drive PASMC hyperproliferation and increased migration. SMC-specific deletion of Bmal1 protected mice from RV dysfunction, pulmonary vascular remodeling, and PAH. EEG/EMG measurements demonstrated that PAH causes poor sleep quality in mice. Lastly, we showed that improving sleep via melatonin delivery and blunting inflammation with clodronate inhibited pulmonary vascular remodeling and PAH. ConclusionsOur study demonstrates that PAH causes poor sleep which in turn induces inflammation, increases PASMC proliferation, and exacerbates PAH. This suggests that the relationship between PAH and poor sleep is a self-amplifying cycle, and that a combination of hypnotic and anti-inflammatory drugs may give PAH patients better clinical outcomes. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIPAH causes poor sleep quality which in turn induces lung inflammation, PASMC proliferation, and exacerbated PAH. C_LIO_LIBmal1 rhythmicity is disrupted, and its expression is increased in lungs of patients with PAH. C_LIO_LISMC-specific deletion of Bmal1 protects from PAH. C_LIO_LIImproving sleep quality and blunting inflammation attenuates PAH. C_LI What Are the Clinical Implications?O_LIBmal1 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIA combination of hypnotic and anti-inflammatory drugs has therapeutic potential to treat PAH. C_LI

pathology↗

bioRxiv2025

A Simultaneous Inhibition of ID1 and ID3 Protects Against Pulmonary Fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are desperately needed. Inhibitor of DNA binding (ID) proteins are regulated by Transforming Growth Factor-{beta}. However, the regulation and the effects of ID proteins in IPF remain poorly understood. We aimed to assess the expression of ID proteins in IPF and determine the effects of ID proteins on human lung fibroblasts (HLF) in vitro and pulmonary fibrosis in vivo. MethodsThe expression of ID proteins in lungs and lung fibroblasts from mice and human patients with pulmonary fibrosis was evaluated. The effects of ID1/ID3 inhibition and overexpression on HLF were assessed. Genetic and pharmacological approaches were used in vivo to determine the role of ID1/ID3 in pulmonary fibrosis. ResultsID1/ID3 levels were elevated in HLFs isolated from pulmonary fibrosis-diseased patients and mice. ID1/ID3 knockdown decreased IPF-diseased HLF proliferation and differentiation into myofibroblasts. Bleomycin-exposed ID1/ID3 KO mice displayed improved lung function and presented with decreased lung fibrosis when compared to WT mice. A pharmacological inhibitor of ID1/ID3 decreased IPF-diseased HLF proliferation and differentiation in vitro and attenuated pulmonary fibrosis in vivo. A lung specific inhibition of ID1/ID3, using adeno-associated viruses expressing short hairpins targeting ID1 and ID3, reversed pulmonary fibrosis in mice. Mechanistically, ID1/ID3 inhibition decreased fibroblast proliferation through cell cycle genes and inhibited fibroblast differentiation through the MEK/ERK pathway. ConclusionsOur data indicate that a simultaneous inhibition of ID1 and ID3 attenuates pulmonary fibrosis. ID1/ID3 inhibition holds potential as a novel therapeutic treatment for IPF.

pathology↗

bioRxiv2025

Paracrine Action of Bone Morphogenetic Protein 3 in Pulmonary Arterial Hypertension

BackgroundDespite recent advancements in the management of pulmonary arterial hypertension (PAH), the disease remains devastating, with limited survival. Although the Bone Morphogenetic Protein (BMP) signaling pathway is known to play an important role in PAH, our current understanding of this pathway remains limited. MethodsWe assessed BMP3 levels in the lungs of mice, rats, and pigs with pulmonary hypertension, and in pulmonary vascular cells from human patients with PAH. We performed in vitro studies on human pulmonary artery smooth muscle cells (hPASMCs) and human pulmonary artery endothelial cells (hPAECs) derived from healthy donors and from patients with PAH. We generated mice with global or SMC-specific deletion of BMP3. Recombinant BMP3 protein and adeno-associated viruses (AAV) were used to overexpress BMP3 in two different models of PAH in rodents. Magnetic resonance imaging, cardiac hemodynamics, morphometric, and histological measurements were performed to evaluate the effects of BMP3 on cardiac function and pulmonary vascular remodeling. ResultsBMP3 is predominantly expressed in PASMCs and is downregulated in PAH. In vitro, conditioned medium from siRNA-BMP3-transfected hPASMCs increased hPAECs migration and proliferation, while PASMC-derived BMP3 inhibited PAH-diseased PAEC dysfunction. In both global and SMC-specific BMP3-deficient mice, exposure to a model of PAH exacerbated cardiac and pulmonary vascular remodeling in middle-aged mice. An intraperitoneally injected recombinant BMP3 prevented and reversed PAH in mice. A lung-targeted overexpression of BMP3, via AAV1-BMP3, reversed pulmonary vascular remodeling and inhibited cardiac dysfunction in mice and rats. Mechanistically, BMP3 activated the BMP/Smad1,5,8 pathway, inhibited the TGF-{beta}/Smad2,3 pathway, and decreased the expression of cell cycle genes in hPAECs and in the lungs of BMP3-treated animals with PAH. ConclusionsOur findings provide evidence that BMP3 overexpression attenuates pulmonary vascular remodeling and inhibits cardiac dysfunction by restoring the balance between the TGF-{beta} and BMP pathways through a cell-cell communication mechanism, offering a novel therapeutic pathway for PAH. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIBMP3 is downregulated in the lungs of mice, rats, and pigs with pulmonary hypertension and in pulmonary artery smooth muscle cells of patients with PAH. C_LIO_LIBMP3 acts as a paracrine factor between pulmonary vascular cells. C_LIO_LIOverexpression of BMP3 decreases pulmonary vascular remodeling and reverses cardiac dysfunction in PAH-diseased rodents. C_LIO_LIBMP3 acts by restoring the balance between the TGF-{beta}/Smad2,3 pathway and the BMP/Smad1,5,8 pathway C_LI What Are the Clinical Implications?O_LIBMP3 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIOverexpressing BMP3 with Adeno-Associated Viruses has therapeutic potential to treat PAH. C_LI

pathology↗

bioRxiv2025

Orally Delivered Milk-Derived Nanovesicles Loaded with Connexin 43 Peptides forTargeted Cardiac Ischemia-Reperfusion Therapy

Extracellular vesicles have emerged as promising nanocarriers for targeted drug delivery, but their therapeutic potential is limited by challenges related to administration route, loading, targeted delivery and production at scale. Here, we report an innovative approach for targeted delivery of therapeutic peptides to injured tissues using milk-derived small extracellular vesicles (mEVs) as an abundant, safe, orally administrable nanoplatform. We demonstrate that a sub-population of mEVs naturally contain Connexin 43 (Cx43) and its Carboxyl-Terminal (CT) polypeptides, which have been shown to play crucial roles in wound healing and tissue repair. Leveraging this intrinsic property, we developed an esterification method to efficiently and uniformly load mEVs with enhanced levels of an exogenous Cx43 CT peptide (CT11 - RPRPDDLEI), as assessed by flow cytometry-based vesicle quantification and mass spectrometry. These engineered mEVs exhibited remarkable injury targeting capabilities, with > 30-fold increases in uptake by injured cells compared to non-wounded cells in vitro and preferential accumulation in wounded tissues in vivo. Notably, CT11-loaded mEVs orally administered after myocardial infarction reduced infarct size by >60% and preserved heart function in a mouse model of ischemia-reperfusion injury. This study represents a significant advance in nanomedicine, demonstrating the utilization of naturally occurring milk-derived extracellular vesicles as an oral delivery system for therapeutic peptides, achieving unprecedented targeting efficiency and efficacy in the treatment of myocardial ischemia-reperfusion injury.

bioengineering↗

bioRxiv2023

Unravelling vulture avoidance tactic of wind turbines combining empirical and simulation data

The increase of wind turbine installations to limit climate change may affect bird populations because of collisions with rotor blades. Birds may respond to wind turbine presence along a gradient of behavioural changes: avoiding the wind farm (macro-scale) or only the wind turbines either by anticipating wind turbine locations (meso-scale) or engaging into last-minute flee attempts after late perception (micro-scale). We investigated the flight response at these three spatial scales of 25 adult griffon vultures (Gyps fulvus) equipped with GPS tags over three years when flying in an area including ten wind farms in the Causses, France. At macro-scale, the population foraging range and habitat use revealed that vultures did not avoid wind farms. To investigate avoidance at meso- and micro-scales we focused on the four mostly visited wind farms. We compared vulture flights to null movement models, based on a method allowing us to keep the correlation between flights and topography while creating movement independent of wind turbine locations. At most sites, vultures did not show avoidance behaviour. Yet, simulations from our agent-based model highlighted that the avoidance pattern detected at one wind farm matched with an anticipated avoidance of turbines, probably linked to the presence of a ridge nearby. Overall, our results suggest wind farm-specific responses by soaring birds as a function of the landscape topography. Thus, stakeholders should carefully consider the wind farm location for siting and designing preventive measures (e.g. improve detection of species not able to avoid turbines in switching off on-demand technologies) to reduce collision risk of soaring birds.

animal behavior and cognition↗

bioRxiv2023

The use of social information in vulture flight decisions

Animals rely on a balance of personal and social information to decide when and where to move next in order to access a desired resource, such as food. The benefits from cueing on conspecifics to reduce uncertainty about resources availability can be rapidly overcome by the risks of within-group competition, often exacerbated toward low-ranked individuals. Being obligate soarers, relying on thermal updrafts to search for carcasses around which competition can be fierce, vultures represent ideal models to investigate the balance between personal and social information during foraging movements. Linking dominance hierarchy, social affinities and meteorological conditions to movement decisions of eight captive vultures, Gyps spp., released for free flights in natural-like soaring conditions, we found that they relied on social information (i.e. other vultures using/having used the thermals) to find the next thermal updraft, especially in unfavourable flight conditions. Low-ranked individuals were more likely to disregard social cues when deciding where to go next, possibly to minimise the competitive risk of social aggregation. These results exemplify the architecture of decision-making during flight in social birds. It suggests that the environmental context, the context of risk and the social system as a whole calibrate the balance between personal and social information use.

animal behavior and cognition↗