1. WISP-1 Regulates Cardiac Fibrosis by Promoting Cardiac Fibroblasts' Activation and Collagen Processing.
- Author
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Li Z, Williams H, Jackson ML, Johnson JL, and George SJ
- Subjects
- Animals, Humans, Mice, Collagen metabolism, Angiotensin II pharmacology, Mice, Knockout, Collagen Type I metabolism, Proto-Oncogene Proteins c-akt metabolism, Male, Signal Transduction drug effects, Mice, Inbred C57BL, CCN Intercellular Signaling Proteins metabolism, CCN Intercellular Signaling Proteins genetics, Fibroblasts metabolism, Fibroblasts pathology, Fibroblasts drug effects, Fibrosis, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins genetics, Myocardium pathology, Myocardium metabolism
- Abstract
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.- Published
- 2024
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