Biology subjects

Halouani, A.

Publications and source records attributed to Halouani, A..

4 recordsLinked to original sources

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↗

bioRxiv2020

Mechanisms of Igf2 inhibition in thymic epithelial cells infected by coxsackievirus CV-B4

Epidemiological studies have evidenced a link between type 1 diabetes (T1D) and infections by enteroviruses, especially with coxsackievirus B4 (CV-B4). CV-B4 is able to infect human and murine thymic epithelial cells (TECs) and, in a murine TEC line, we have shown that the diabetogenic strain CV-B4 E2 decreases transcription of insulin-like growth factor 2 gene (Igf2), coding for the self-peptide of the insulin family. Here we show that in CV-B4 infection of mice alters Igf2 transcripts isoforms in TECs, followed by a decrease of pro-IGF2 precursor in the thymus. CV-B4 infection of a murine TEC line decreases Igf2 P3 promoter activity by targeting the region -68 to -22 upstream of the transcription start site (TSS) whereas Igf2 transcripts stability is not affected, pointing towards a regulation of Igf2 transcription. Our data also show that CV-B4 decreases IL-6/STAT3 signaling in vitro. This study provides new knowledge about the regulation of intrathymic Igf2 transcription by CV-B4 and reinforces the hypothesis that CV-B4 infection of the thymus could break central self-tolerance of the insulin family by decreasing Igf2 transcription and IGF2 presentation in thymus epithelium. IMPORTANCECoxsackievirus B4 represents one of the most important environmental factors associated to type 1 diabetes, autoimmune disease for which no curative treatment exist. The diabetogenic strain Coxsackievirus B4 E2 was previously shown to decrease Igf2 expression, important player for central tolerance towards insulin, in a thymic epithelial cell line. The understanding of Igf2 regulation mechanisms during coxsackievirus B4 infection represents an interest for the understanding of central tolerance development but also for Igf2 transcriptional regulation itself, still poorly understood. Here we demonstrate that, some transcripts isoforms of Igf2 are also decreased in thymic epithelial cells in vivo. Moreover, we show that this decrease is induced by an alteration of specific regions of Igf2 P3 promoter and may be linked by a decrease of STAT3 signaling. In fine we hope that this work could lead to future therapies leading to reprogramming central tolerance towards {beta} cells antigens via Igf2 expression.

microbiology↗