Abstract P3127: Wnt1-inducible Signalling Pathway Protein 1 Contributes To Vascular Fibrosis By Promoting Fibroblasts Phenotypic Switch And Extracellular Matrix Deposition

Abstract

Background: Vascular fibrosis is linked with many diseases, including hypertension. Upon pathophysiological stimulation, fibroblasts undergo phenotypic switch and increase extracellular matrix (ECM) synthesis and deposition. Wnt1-inducible signalling pathway protein 1 (WISP-1) is a growth factor implicated in fibrotic remodelling. We tested the hypothesis that WISP-1 induces cardiac fibroblast activation and increases ECM deposition, thereby contributing to vascular fibrosis in hypertension. Methods and Results: Primary human cardiac fibroblasts (HCFs) were treated with recombinant WISP-1. Western blotting analysis showed that WISP-1 treatment for 30 minutes activated Akt pathway (phospho-Akt:total-Akt, fold change: 1.33±0.14 vs. 1.00±0, n=9, P <0.05). WISP-1 induced Akt phosphorylation was inhibited by an integrin β1 blocking antibody (phospho-Akt:total-Akt, fold change, 0.52±0.12 vs. 1.00±0, n=5, P <0.05). WISP-1 treatment for 24 hours induced collagen 1 maturation in conditioned media and coincided with decreased meprin α metalloproteinase protein levels (fold change: 0.44±0.14 vs. 1.00±0, n=5, P <0.05). The collagen maturation was inhibited by a zinc-mediated proteinase inhibitor (GM6001) or an Akt inhibitor. Additionally, immunocytochemistry analysis illustrated that 24-hour WISP-1 treatment increased the percentage of α-smooth muscle actin-positive HCFs compared to the control (1.89±0.37 vs. 1.00±0, n=8, P <0.05). In vivo , WISP-1 knockout mice exhibited reduced collagen 1 content (0.39±0.09 vs. 1.19±0.25, n=5-7, P <0.05) and proteoglycan content (2.20±0.37 vs. 6.22±1.10, n=5-7, P <0.05,) in the perivascular area compared to their wild-type control after 28 days angiotensin II (1000ng/kg/min) infusion. Conclusions: WISP-1 activates cardiac fibroblasts via integrin β1-Akt pathway and meprin α metalloproteinase, thereby inducing fibroblast phenotypic switch and promoting collagen deposition. Deletion of WISP-1 alleviated hypertension induced vascular fibrosis in vivo . Modulation of WISP-1 levels may be beneficial for attenuating the effects of hypertension on vascular fibrosis, and could provide potential therapeutic targets in clinical treatment.