Biology subjects

Hadzic, S.

Publications and source records attributed to Hadzic, S..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema

Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic inflammation, emphysema, and mild pulmonary hypertension (PH). Oxidative/nitrosative stress are key drivers, but specific mitochondrial mechanisms remain unclear. We show increased expression of the regulatory mitochondrial cytochrome c oxidase subunit 4 isoform 2 (COX4I2) in an early murine model and human COPD. After 8 months of cigarette smoke exposure, Cox4i2-/- mice were completely protected from emphysema but not from PH, associated with reduced nitrosative stress, inflammation, and apoptosis. Using a novel Cox4i2 reporter mouse and in situ hybridization of human lungs, COX4I2 was detected in precapillary ACTA2+ cells and capillary pericytes. COX4I2 promotes mitochondrial reactive oxygen species (mtROS) production in these cells, thereby enhancing neutrophil migration and alveolar type II cell apoptosis, and modulates angiogenesis. In contrast to Cox4i2-/-, mitochondria-targeted antioxidant MitoQ reversed emphysema and PH, suggesting pericyte-specific regulation of COPD pathologies and mtROS inhibition as a therapeutic approach in COPD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/703513v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@83bca4org.highwire.dtl.DTLVardef@d5ebaborg.highwire.dtl.DTLVardef@632d1borg.highwire.dtl.DTLVardef@1267a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Cigarette smoking upregulates vascular expression of the novel atherosclerosis risk factor ADAMTS-7

BackgroundCigarette smoking is an established risk factor for coronary artery disease (CAD) and myocardial infarction. Genetic variants in the extracellular matrix protease ADAMTS-7 were also identified to increase CAD risk. Notably, ADAMTS7 represents the only genomic locus that revealed a gene-environment interaction with smoking. The underlying mechanisms of this interaction remain unclear. Methods and ResultsIn a murine model, cigarette smoke exposure (CSE) led to an upregulation of vascular ADAMTS7 expression in wild type (WT) C57BL/6J mice. ADAMTS7 upregulation was also found in carotid plaques from ever-smokers undergoing carotid endarterectomy in humans. Bulk RNA sequencing of lung tissues from WT mice exposed to CS revealed a downregulation of 20 and an upregulation of 173 transcripts. Among upregulated transcripts in smoking-exposed lungs, we found C-C motif chemokine ligand 17 (CCL17), which was likewise upregulated in plasma from smoking mice and humans. In vitro, recombinant CCL17 upregulated ADAMTS7 expression in primary vascular smooth muscle cells (VSMC), which was inhibited secondary to silencing of CCL17s bona fide receptor C-C Motif Chemokine Receptor 4 (CCR4). Conditioned media from CCL17-stimulated VSMC lacking ADAMTS-7 showed reduced release of inflammatory cytokines by endothelial cells (EC), reduced EC activation, and monocyte-to-EC adhesion. In proatherogenic Apoe-/- mice exposed to CS, more numerous neutrophils, inflammatory monocytes, and macrophages were found in atherosclerotic plaques as compared to room air exposition. This effect was blunted in Apoe-/-Adamts7-/- mice. ConclusionsFor the first time, our findings link CSE to vascular inflammation via CCL17-mediated upregulation of the CAD risk factor ADAMTS7 and provide a mechanistic explanation for the gene-environment interaction between CS and ADAMTS7 in CAD. Targeting ADAMTS-7 might be a promising therapeutic strategy irrespective of smoking status. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/685237v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1d8366eorg.highwire.dtl.DTLVardef@1dda3feorg.highwire.dtl.DTLVardef@39a4bcorg.highwire.dtl.DTLVardef@6e58b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Lineage-tracing of Acta2+ cells in aged mice during lung fibrosis formation and resolution supports the lipofibroblasts to myofibroblast reversible switch

Idiopathic pulmonary fibrosis (IPF) develops mostly in old man and is characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs) leading to lung failure. Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place, the later limiting the clinical relevance of this model for IPF. In young mice, we previously reported that aMYFs captured during fibrosis formation differentiate towards a lipofibroblast (LIF)-like phenotype during resolution. In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution, as a more relevant model for IPF and examined the heterogeneity and fate of aMYFs at different time points. Alveolosphere assay were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Data mining of human mesenchymal cells from IPF and control datasets were also performed to decipher the heterogeneity of aMYFs and investigate differentiation trajectories during fibrosis formation. Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. We report that aMYFs consist of four subclusters displaying unique pro-alveologenic versus pro-fibrotic profiles. Alveolar fibroblasts displaying a high LIF-like signature largely constitute both the origin and fate of aMYFs during fibrosis formation and resolution, respectively. The heterogeneity of aMYFs is conserved in humans and a significant proportion of human aMYFs displays a high LIF signature. In conclusion, our data indicate that the cellular and molecular bases of aMYFs formation and differentiation towards the LIF phenotype are conserved between young and old mice. Importantly, our work identifies a subcluster of aMYFs that is potentially relevant for future management of IPF.

pathology↗