Translational Health Sciences, Bristol Medical School, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
Bristol Heart Institute, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, UK.
Cells. 2024 Jun 6;13(11):989. 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.
高血压可诱导心肌成纤维细胞（CFs）发生表型转化和胶原沉积，从而引起心肌纤维化重塑。本研究旨在验证 Wnt1 诱导信号通路蛋白-1（WISP-1）是否可促进 CFs 的表型转化、I 型前胶原的合成以及体内纤维化重塑。我们用 WISP-1（500ng/ml）处理人 CFs（HCFs，n=16）24h 后，发现 WISP-1 可诱导 CFs 发生表型转化（α-平滑肌肌动蛋白阳性），并使 I 型前胶原裂解为中间形式的胶原（pC-胶原），从而促进胶原成熟。WISP-1 诱导的胶原加工是通过整合素 β1 和整合素金属蛋白酶与血栓反应蛋白 2（ADAMTS-2）介导的 Akt 磷酸化实现的。我们构建了 WISP-1 野生型（WISP-1）和 WISP-1 敲除（WISP-1）小鼠（n=5-7），并用血管紧张素 II（AngII，1000ng/kg/min）对其进行 28 天的皮下输注。免疫组化结果显示，与 WISP-1 小鼠相比，WISP-1 缺失可减少冠状动脉血管周围区域的 I 型胶原沉积，因此，WISP-1 缺失可减轻 AngII 诱导的体内心肌纤维化。综上所述，我们的研究结果表明，WISP-1 通过整合素 β1-Akt 信号通路促进 CFs 的激活，通过 ADAMTS-2 诱导胶原加工和成熟，是心脏纤维化重塑的关键介质。因此，调节 WISP-1 水平可能为临床治疗提供潜在的治疗靶点。
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