Biology subjects

Bisserier, M.

Publications and source records attributed to Bisserier, M..

4 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↗

bioRxiv2026

Sotatercept Reverses SIN3a Deficiency-Driven PAH by Reprogramming BMPR2/TGF-β-HIF-1α Signaling Pathways

BackgroundPulmonary arterial hypertension is a progressive and fatal cardiopulmonary disease marked by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), pathological vascular remodeling, and ultimately right heart failure. Dysregulated BMPR2 signaling is a central molecular hallmark of PAH and is often associated with epigenetic suppression of BMPR2 expression. Switch-independent 3a (SIN3a), a transcriptional co-regulator and chromatin-modifying scaffold protein, has emerged as a key regulator of BMPR2 expression, yet its role in PAH pathogenesis remains poorly defined. MethodsWe generated smooth muscle cell-specific SIN3a knockout mice (SIN3aSMC-/-) and subjected them to the Sugen/hypoxia protocol to induce PAH. A cohort received Sotatercept treatment. In parallel, human PASMCs engineered to overexpress SIN3a were exposed to TGF{beta}1 or hypoxia (1% O2) in vitro. Comprehensive transcriptomic profiling and pathway analyses identified molecular networks regulated by SIN3a and Sotatercept. Hemodynamic measurements and detailed morphometric analyses were used to assess disease severity and treatment response. ResultsSIN3a overexpression in PASMCs suppressed hypoxia-inducible factor-1 and TGF-{beta}/SMAD2/3 signaling, restored BMPR2 expression, and activated canonical BMP signaling through SMAD1/5/9 phosphorylation, while reducing pro-inflammatory, oxidative, and fibrotic gene programs. Transcriptomic analyses revealed that SIN3a and Sotatercept converge on gene networks that regulate BMPR2 signaling, ID isoforms, extracellular matrix remodeling, oxidative stress, and inflammation. In vivo, smooth muscle-specific SIN3a deletion exacerbated Sugen/hypoxia-induced PAH, increasing right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling, and fibrosis. Sotatercept treatment reversed these pathological features, restored SIN3a and BMPR2 expression, reactivated BMP signaling, and attenuated HIF-1 and TGF-{beta} signaling in SIN3a-deficient mice. ConclusionsSIN3a is a central epigenetic regulator of PASMC homeostasis that integrates oxidative stress, inflammation, and fibrotic signaling. Loss of SIN3a accelerates PAH progression, whereas Sotatercept restores SIN3a expression, rebalances BMPR2 and TGF-{beta} signaling, and attenuates pulmonary vascular remodeling and right ventricular dysfunction. Together, these findings identify SIN3a as a disease-relevant therapeutic target and support the use of Sotatercept as a disease-modifying approach for pulmonary vascular disease.

molecular biology↗

bioRxiv2025

Epigenetic Activation of Endothelial Smurf1 via EP300-Mediated H3K27ac Disrupts BMPR2 Signaling in Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by pulmonary endothelial dysfunction, vascular remodeling, and right ventricular failure. Despite recent advances, the underlying molecular mechanisms remain incompletely understood, and curative treatments are still lacking. Loss of BMPR2 signaling is a hallmark of PAH pathogenesis, yet the mechanisms leading to BMPR2 destabilization are not fully defined. Smad ubiquitination regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, has been implicated in the degradation of BMPR2 and downstream signaling proteins; however, the regulation of Smurf1 and its therapeutic potential remain largely unexplored. MethodsWe assessed Smurf1 expression in lung tissues from PAH patients, experimental animal models, and pulmonary artery endothelial cells (PAECs). Epigenetic regulation of Smurf1 was examined using ChIP-qPCR, EP300 gain- and loss-of-function studies, and pharmacological inhibition with the selective EP300 inhibitor A485. Functional consequences of Smurf1 inhibition were evaluated in vitro using transcriptomic profiling, proliferation assays, and BMPR2-Smad signaling analyses. In vivo therapeutic efficacy was tested in monocrotaline (MCT)-induced PAH rats treated with the selective Smurf1 inhibitor Smurf1-IN-A01. ResultsSmurf1 expression was elevated in PAH patient lungs, experimental models, and PAECs. Increased histone H3K27 acetylation and EP300 occupancy at the Smurf1 promoter implicated epigenetic activation. EP300 inhibition reduced H3K27ac enrichment, suppressed Smurf1 expression, and restored BMPR2 signaling. Smurf1 blockade with Smurf1-IN-A01 reprogrammed the transcriptomic landscape of PAH-PAECs, downregulating inflammatory, fibrotic, and angiogenic gene networks. Functionally, Smurf1 inhibition decreased pathological endothelial proliferation and enhanced BMPR2-mediated Smad1/5/9 activation. In vivo, Smurf1- IN-A01 improved pulmonary hemodynamics, reduced vascular remodeling and fibrosis, and restored BMPR2 signaling in MCT-PAH rats. ConclusionsOur study identifies Smurf1 as an epigenetically regulated driver of endothelial dysfunction and vascular remodeling in PAH. Targeting Smurf1 restores BMPR2 signaling, reprograms pathogenic processes, and offers a novel therapeutic strategy for PAH.

molecular biology↗

bioRxiv2024

Pharmacological Inhibition of Epac1 Protects against Pulmonary Fibrosis by Blocking FoxO3a Neddylation

BackgroundIdiopathic Pulmonary fibrosis (IPF) is characterized by progressive scarring and fibrosis within the lungs. There is currently no cure for IPF; therefore, there is an urgent need to identify novel therapeutic targets that can prevent the progression of IPF. Compelling evidence indicates that the second messenger, cyclic adenosine monophosphate (cAMP), inhibits lung fibroblast proliferation and differentiation through the classical PKA pathway. However, the contribution of the exchange protein directly activated by cAMP 1 (Epac1) to IPF pathophysiological processes is yet to be investigated. ObjectiveTo determine the role of the cAMP-binding protein Epac1 in the progression of IPF. MethodsWe used lung samples from IPF patients or healthy controls, mouse lung samples, or lung fibroblast isolated from a preclinical mouse model of PF induced by bleomycin intratracheal injection. The effect of bleomycin (BLM) treatment was determined in Epac1 knock-out mice or wild-type littermates. Epac1 expression was modulated in vitro by using lentiviral vectors or adenoviruses. The therapeutic potential of the Epac1-selective pharmacological inhibitor, AM-001, was tested in vivo and in vitro, using a bleomycin mouse model of PF and an ex vivo precision-cut lung slices (PCLs) model of human lung fibrosis. ResultsEpac1 expression was increased in the lung tissue of IPF patients, in IPF-diseased fibroblasts and in BLM-challenged mice. Furthermore, Epac1 genetic or pharmacological inhibition with AM-001 decreased normal and IPF fibroblast proliferation and the expression of profibrotic markers, SMA, TGF-{beta}/SMAD2/3, and interleukin-6 (IL-6)/STAT3 signaling pathways. Consistently, blocking Epac1 protected against BLM-induced lung injury and fibrosis, suggesting a therapeutic effect of Epac1 inhibition on PF pathogenesis and progression. Global gene expression profiling revealed a decrease in the key components of the profibrotic gene signature and neddylation pathway in Epac1-deficient lung fibroblasts and IPF human-derived PLCs. Mechanistically, the protective effect of Epac1 inhibition against PF development involves the inhibition of FoxO3a neddylation and its subsequent degradation by NEDD8, and in part, by limiting the proliferative capacity of lung-infiltrating monocytes. ConclusionsWe demonstrated that Epac1 is an important regulator of the pathological state of fibroblasts in PF and that small molecules targeting Epac1 can serve as novel therapeutic drugs against PF.

physiology↗