CTHRC1 mitigates dystrophic aortic valve calcification by suppressing foamy macrophage-mediated inflammatory remodeling

Although aortic stenosis (AS) represents a major cardiovascular burden, the molecular mechanisms underlying aortic valve calcification remain unclear. Spatial transcriptomic analysis of injured valve leaflets identified Cthrc1 (collagen triple helix repeat containing 1) as a prominently induced factor within the valvular interstitium. CTHRC1 elevation in expanded valvular interstitial cells (VICs) of thickened murine valve leaflets was validated by immunohistochemistry, and similar CTHRC1 upregulation was confirmed in human stenotic aortic valves. Lineage-tracing analyses demonstrated that the expanded VIC population in thickened murine valve leaflets following wire injury was derived predominantly from PDGFRβ-positive interstitial cells, with little contribution from endothelial cells. Although hemodynamic alterations were comparable between Cthrc1 −/− and wild-type AS mice, Cthrc1 deficiency markedly exacerbated valvular calcification during the chronic phase. Further spatial transcriptomic analyses of Cthrc1 −/− AS mice revealed extensive accumulation of Galectin-3-positive foamy macrophages within the interstitial space of stenotic valves in Cthrc1 −/− mice compared with wild-type controls. Moreover, stenotic valves from Cthrc1 −/− mice exhibited depletion of respiratory-chain signatures and upregulation of cell death–associated pathways, suggesting that CTHRC1, transiently induced during the acute phase following valvular endothelial injury, protects against subsequent dystrophic calcification.