PTN secreted by cardiac fibroblasts promotes myocardial fibrosis and inflammation of pressure overload-induced hypertrophic cardiomyopathy through the PTN-SDC4 pathway

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) with key pathologic processes including myocardial necrosis, fibrosis, inflammation, and hypertrophy, which are involved in heart failure (HF), stroke, and even sudden death. Our aim was to explore the communication network among various cells in the heart of transverse aortic constriction (TAC) surgery induced HCM mice.

Materials and methods: Single-cell RNA-seq data of GSE137167 was downloaded from the Gene Expression Omnibus (GEO) database. Seurat was used to perform the standard workflow. CellChat was utilized to compute the cell-cell interaction network and analyze the ligand-receptor pairs. Weighted gene co-expression network analysis (WGCNA) was conducted to identify gene co-expression modules. In vitro and in vivo studies were performed to verify bioinformatic analysis findings through real-time quantitative PCR (RT-qPCR), Edu staining, transwell assay, western blot, immunofluorescence assay, CCK-8, hematoxylin and eosin (H&E) staining, and echocardiography based on TAC mouse model.

Key findings: Our results showed that after TAC surgery, the interaction between cardiac fibroblasts and macrophages was very common, and the increasing pleiotrophin (PTN) ligand secreted by cardiac fibroblasts could promote the self-proliferation or invasion for myocardial fibrosis as well as stimulate the inflammatory response of macrophages to contribute TAC surgery induced HCM through acting on Syndecan 4 (SDC4) receptor.

Significance: Our study demonstrates that PTN derived from cardiac fibroblasts may play potential role in pressure overload-induced HCM through activating the PTN-SDC4 pathway in cardiac fibroblasts and macrophages, which may be a potential therapeutic target for pressure overload-induced HCM patients.