Targeting fibroblast CTHRC1 ameliorates cardiac fibrosis and dysfunction by suppressing cardiomyocyte NLRP3 inflammasome activation
X Wang, J X Chen, W J Tian, Y X CaiAbstract
Background
Heart failure (HF) is the common end-stage of multiple cardiovascular diseases with high-rate rehospitalization and mortality despite limited therapies. Pathological fibrotic remodeling driven by cardiac fibroblast (CF) activation is central to its initiation and progression. Targeted elimination of pathological CFs is considered a promising strategy to ameliorate adverse remodeling.
Methods
Datasets concerning cardiac maladative remodeling and dysfunction were downloaded from the Gene Expression Omnibus database to screen potential mediators of pathological cardiac fibroblasts. Serum samples and clinical characteristics of healthy controls and patients with heart failure were analyzed. Cthrc1 knockout mice, cardiac fibroblast-specific Cthrc1 knockout mice, and anti-CTHRC1 mAb–treated C57BL/6 mice were infused angiotensin II/phenylephrine (Ang-II/PE) for 4 weeks for cardiac fibrosis. In vitro, neonatal rat ventricular cardiomyocytes (NRCM), fibroblasts (NRCF), and human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs) were used to investigated the role of CTHRC1. Unbiased single-nucleus and bulk RNA sequencing analyses, functional assays and Co-IP coupled with mass spectrometry analysis were conducted to elucidate the direct effect of CTHRC1 in cardiac fibrosis.
Results
CTHRC1 (collagen triple helix repeat–containing 1) is an essential for cardiac fibrosis and mechanical dysfunction of pathologically stressed hearts. CTHRC1 is elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers. In mice, cardiac stress activates fibroblasts to express and secrete CTHRC1 into the circulation, triggering fibrosis and maladaptive remodeling of stressed hearts. Antibody-mediated inhibition or genetic disruption of CTHRC1 greatly reduces stress-induced cardiac fibrosis, improving systolic and diastolic functions. Mechanistically, CTHRC1 binds to ADAM17 receptor on cardiomyocytes, activates the Nuclear Factor-kappa B signaling pathway and NLRP3 inflammasome, thereby promoting myocardial pyroptosis and dysfunction.
Conclusions
These findings nominate CTHRC1 as a critical regulator of pathological CFs and triggers inflammatory gene expression and activation of the NLRP3 inflammasome in CMs. Collectively, our preclinical findings and a conserved human data provide mechanistic rationale and preclinical proof-oconcept for targeting CTHRC1 to improve cardiac fibrosis and dysfunction, positioning CTHRC1 as a potential therapeutic target and diagnostic biomarker for heart failure in clinical practice.