WISP-1 Regulates Cardiac Fibrosis by Promoting Cardiac Fibroblasts' Activation and Collagen Processing

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 11; p. 989
• Main Authors: Li, Ze, Williams, Helen, Jackson, Molly L, Johnson, Jason L, George, Sarah J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.06.2024; MDPI
• Subjects: Actin; AKT protein; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animals; Antibodies; cardiac fibroblasts; cardiac fibrosis; CCN Intercellular Signaling Proteins - genetics; CCN Intercellular Signaling Proteins - metabolism; Collagen; Collagen (type I); Collagen - metabolism; Collagen Type I - metabolism; Coronary artery; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Health aspects; Heart; Humans; Hypertension; Immunohistochemistry; Integrins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motility; Myocardium - metabolism; Myocardium - pathology; Penicillin; Pharmaceutical industry; Phosphorylation; Polymerase chain reaction; Procollagen; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Signal Transduction - drug effects; Smooth muscle; Therapeutic targets; Thrombospondin; WISP-1/CCN4; United States; United Kingdom; Germany; United Kingdom > UK; United States > US; collagen; WISP-1/CCN4; cardiac fibroblasts; cardiac fibrosis
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13110989

Hypertension induces cardiac fibrotic remodelling characterised by the phenotypic switching of cardiac fibroblasts (CFs) and collagen deposition. We tested the hypothesis that Wnt1-inducible signalling pathway protein-1 (WISP-1) promotes CFs' phenotypic switch, type I collagen synthesis, and in vivo fibrotic remodelling. The treatment of human CFs (HCFs, n = 16) with WISP-1 (500 ng/mL) induced a phenotypic switch (α-smooth muscle actin-positive) and type I procollagen cleavage to an intermediate form of collagen (pC-collagen) in conditioned media after 24h, facilitating collagen maturation. WISP-1-induced collagen processing was mediated by Akt phosphorylation via integrin β1, and disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2). WISP-1 wild-type (WISP-1 ) mice and WISP-1 knockout (WISP-1 ) mice (n = 5-7) were subcutaneously infused with angiotensin II (AngII, 1000 ng/kg/min) for 28 days. Immunohistochemistry revealed the deletion of WISP-1 attenuated type I collagen deposition in the coronary artery perivascular area compared to WISP-1 mice after a 28-day AngII infusion, and therefore, the deletion of WISP-1 attenuated AngII-induced cardiac fibrosis in vivo. Collectively, our findings demonstrated WISP-1 is a critical mediator in cardiac fibrotic remodelling, by promoting CFs' activation via the integrin β1-Akt signalling pathway, and induced collagen processing and maturation via ADAMTS-2. Thereby, the modulation of WISP-1 levels could provide potential therapeutic targets in clinical treatment.