CTHRC1 is a new therapeutic target and serum diagnostic biomarker for aortic dissection

Abstract

Aortic dissection (AD) is a cardiovascular disease with rapid onset and extremely high short-term mortality, currently lacking specific peripheral blood-based biomarkers and effective treatments. Here, our analysis of AD samples from animal models and human patients revealed elevated blood levels of CTHRC1, a protein secreted by vascular fibroblasts. Furthermore, CTHRC1 regulates the phenotypic switch of vascular smooth muscle cells (VSMCs) during arterial remodeling by binding to ADAM9 on the VSMC membrane, activating the ERK1/2 signaling pathway, and promoting a contractile-to-synthetic transition. In Ang-II/BAPN induced mouse models, genetic ablation or antibody-mediated blockade of CTHRC1 effectively prevented AD development. These findings unveil CTHRC1 as a critical regulator of VSMC phenotype and aortic structural integrity via the ERK1/2 pathway, suggesting its potential as a novel serum diagnostic biomarker for AD diagnostic and a promising therapeutic target. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/649636v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@6a3f14org.highwire.dtl.DTLVardef@15353e7org.highwire.dtl.DTLVardef@1a9928forg.highwire.dtl.DTLVardef@1d4ef3d_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefCTHRC1 is aberrantly expressed in aortic adventitial fibroblasts from dissected aortas and function as an exocrine mediator that induces phenotypic switching of vascular smooth muscle cells. A monoclonal antibody targeting CTHRC1 demonstrates therapeutic potential in mouse models of aortic dissection. HighlightsO_LICTHRC1 is highly expressed in aortic adventitial fibroblasts from dissected aortas C_LIO_LICTHRC1 interacts with ADAM9 to induce phenotypic switching of VSMCs C_LIO_LIAn anti-CTHRC1 antibody inhibits aortic dissection formationinvivo C_LIO_LIElevated levels of serum CTHRC1 can be used to identify AD in patients presenting with chest pain C_LI