Search bioRxiv⌕ Search

Biology subjects

Veizades, S.

Publications and source records attributed to Veizades, S..

2 recordsLinked to original sources
bioRxiv2026

KCa3.1 Drives Pro-Fibrotic Activation and Represents a Novel Therapeutic Target in Aortic Stenosis

IntroductionAortic stenosis (AS) is characterised by progressive aortic valve (AV) leaflet fibrosis and calcification, yet no medical therapies exist to slow disease progression. AV interstitial cells (VICs) that differentiate into myofibroblasts are central drivers of fibrosis. The Ca2+-activated K+ channel KCa3.1 promotes pro-fibrotic signalling in several fibrotic diseases, however its role in AS remains unknown. MethodsKCa3.1 protein expression was examined in paraffin embedded tissue by Immunohistochemistry from control and AS valve tissue. VICs were isolated, cultured and phenotypically characterised as myofibroblasts from AV tissue obtained from patients with severe tricuspid AS undergoing surgical AV replacement (n=19). KCa3.1 mRNA and protein expression were assessed by qRT-PCR and immunohistochemistry, and functional channel activity confirmed using patch-clamp electrophysiology. The effects of transforming growth factor-{beta}1 (TGF{beta}1) stimulation and pharmacological inhibition with the selective KCa3.1 blocker senicapoc were examined. ResultsImmunoreactive KCa3.1 channels and smooth muscle actin were detected in both control and AS aortic valve tissue, localised to elongated, nucleated interstitial cells, with significantly higher expression observed in AS tissue compared to control. Isolated VICs exhibited an activated myofibroblast phenotype, expressing THY-1, vimentin, collagen and -smooth muscle actin (SMA) (n=9). Myofibroblasts expressed KCa3.1 mRNA and protein and demonstrated functional plasma membrane channels. TGF{beta}1 stimulation increased KCa3.1, SMA and collagen type I mRNA expression, while KCa3.1 blockade with senicapoc (100 nM) significantly attenuated TGF{beta}1-induced SMA expression, stress fibre formation and collagen gel contraction. Senicapoc had no effect on myofibroblast proliferation or migration. ConclusionsWe show for the first time that functional KCa3.1 channels are expressed in human AS tissue and AV myofibroblasts, where they regulate myofibroblast contraction, -SMA expression, and differentiation, promoting pro-fibrotic activity. These responses are attenuated by the selective KCa3.1 inhibitor senicapoc. Given its established safety in phase 3 clinical trials, KCa3.1 inhibition represents a promising and readily translatable anti-fibrotic therapeutic strategy for AS.

cell biology↗
bioRxiv2025

A Human Single-cell Atlas Identifies OLR1+ Scar-associated Macrophages as a Therapeutic Target for Chronic Liver Disease

Chronic liver disease (CLD) is a major global healthcare problem. Irrespective of cause, chronic damage to the liver results in fibrosis, which is associated with adverse clinical outcomes. Immune cells, in particular monocyte-derived macrophages (MDMs), are key regulators of fibrosis and represent an attractive therapeutic target for CLD. However, it has remained unclear which specific subpopulation of MDMs drives pro-inflammatory and pro-fibrotic functions in human CLD and how they might be selectively modulated. Here, we generate an annotated human liver single cell atlas from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. Leveraging large patient and cell numbers, our atlas resolves rare liver cell states and distinguishes two types of disease-expanded scar-associated macrophages (SAMac), including a specific subpopulation with a pro-inflammatory pro-fibrotic phenotype. The scavenger receptor OLR1 was enriched in pro-inflammatory SAMacs and high hepatic OLR1 expression was associated with increased mortality in CLD patients. A corresponding monocyte-derived OLR1+ SAMac subpopulation expanded in a mouse model of CLD and exhibited a pro-inflammatory phenotype based on single-cell RNA-seq, single-cell ATAC-seq, and flow cytometry analyses. Primary human OLR1+ MDMs promoted fibrogenic signalling in multilineage liver spheroid cultures, whilst specific targeting of OLR1 reduced IL-1{beta} production by human macrophages and attenuated myofibroblast activation. Overall, our annotated human liver single-cell atlas provides a valuable reference to study disease-associated cell states in CLD. We utilise this resource to identify a distinct pro-inflammatory subpopulation of SAMacs and highlight OLR1 as a potential therapeutic target to specifically modulate SAMac function and attenuate liver fibrosis.

immunology↗