Wnt signalling plays a key role in the physiology of cardiac development and pathogenesis of cardiovascular disease. Cardiac fibrosis is characterised by the net accumulation of extracellular matrix proteins in the heart, and has a detrimental effect on cardiac function. Wnt1-inducible signalling pathway protein-1 (WISP-1) is a crucial downstream growth factor of Wnt signalling which is involved in fibrotic remodelling. In order to investigate whether the deletion of WISP-1 attenuates angiotensin II (Ang II) induced cardiac fibrosis, male Apo-E-/- WISP-1+/+ mice (single knockout mice, SKO mice, n=7) and male Apo-E-/- WISP-1-/- mice (double knockout mice, DKO mice, n=6) were infused with Ang II (1000 ng/kg/min) using mini-osmotic pumps for 4 weeks. Proteoglycan and collagen content in the heart sections of the mice were measured using alcian blue staining and immunohistochemical staining respectively. Human cardiac fibroblasts (HCFs) were used in vitro to demonstrate whether WISP-1 upregulates collagen synthesis. mRNA levels were analysed using quantitative PCR. Protein levels in cell lysates and concentrated conditioned media of cultured HCFs were assessed using Western blotting analysis. Values are presented as means ± SEM, compared by Mann-Whitney U test or Kruskal-Wallis H tests. Increased proteoglycan content (4.97±0.87 vs. 0.89±0.40, p<0.05) and collagen type 1 content (1.07±0.27 vs. 0.29±0.06, p<0.05) were detected in the SKO + Ang II mice compared to the SKO controls. However, WISP-1 deletion attenuated the profibrotic effect of Ang II (proteoglycan content: 2.56±1.27 (DKO + Ang II) vs. 4.97±0.87 (SKO + Ang II), p<0.05). Treatment of HCFs with WISP-1 did not alter the collagens expression in cell lysates, whereas an additional form of collagen with smaller molecular weight was observed in concentrated conditioned media due to collagens being cleaved. A broad spectrum MMP inhibitor abrogated the collagen cleavage induced by WISP-1. In addition, WISP-1 treatment significantly decreased TIMP-2 mRNA level (0.88±0.04 vs. 1.00±0.00, n=6) compared to the control group. In conclusion, WISP-1 is a pivotal mediator in Ang II induced cardiac fibrosis. These effects are dependent on the regulation of cardiac fibroblasts collagen processing, possibly via the mediation of expression and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).