Caldesmon-1–mediated actin dynamics is essential for osteogenic differentiation of aortic valve interstitial cells

TL;DR

This study shows that caldesmon-1 (CALD1) is important for the development of aortic valve disease by regulating cell shape and bone-like changes in valve cells.

Contribution

The study identifies CALD1 as a novel regulator of valvular interstitial cell osteogenic differentiation in calcified aortic valve disease.

Findings

CALD1 is upregulated in calcified aortic valve stenosis and co-localizes with myofibroblast markers.

CALD1 depletion impairs actin polymerization, cell morphology, and osteoblast differentiation in valve cells.

CALD1 positively regulates osteogenic genes like RUNX2 and ALPL during disease progression.

Abstract

The precise molecular pathways driving fibrosis and calcification in aortic valve leaflets remain poorly defined. Here, we present the first data indicating a role for caldesmon-1 (CALD1) in calcified aortic valve disease (CAVD) pathogenesis. Analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets revealed that CALD1 shows prominent upregulation in aortic valve stenosis (AS) cases when compared to normal subjects. Histological examination demonstrated that CALD1 protein expression is elevated in calcified AS valves and co-localises with α-smooth muscle actin (a myofibroblast biomarker) and vimentin, indicating its association with activated valvular interstitial cells (VICs). Bioinformatic analysis showed that CALD1-positive cells predominantly synthesize extracellular matrix components, including COL1A1. Functional experiments using CALD1-depleted VICs revealed that CALD1 is required for maintaining spindle-shaped morphology, actin polymerisation, and proliferative capacity. Moreover, CALD1 loss significantly impaired osteoblast differentiation and attenuated VIC calcification. Bulk RNA-seq combined with pathway analysis demonstrated that CALD1-mediated actin polymerisation positively regulates key osteogenic and valvulopathy-related genes, including RUNX2 and ALPL. Collectively, these findings identify CALD1 as a novel regulator of VIC phenotypic plasticity and osteogenic transition during CAVD progression, providing mechanistic insight and a target for potential AS therapy.

The online version contains supplementary material available at 10.1038/s41598-026-39938-x.

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