Wnt1-induced secreted protein 1 (WISP-1) is a member of the CCN family of growth factors, and is expressed in the heart at low basal levels. The purpose of this study was to investigate whether WISP-1 is upregulated in post-infarct myocardium, and whether WISP-1 exerts pro-hypertrophic and mitogenic effects stimulating myocyte hypertrophy, fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25g) mice underwent permanent occlusion of the LAD coronary artery. mRNA and protein levels were analyzed by Northern and Western blot. Cardiomyocyte hypertrophy was quantified by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, and soluble collagen release by Sircol assay. A time-dependent increase in WISP-1 expression was detected in vivo in the non-infarct zone of the LV, which peaked at 24 h (3.1-fold, P<0.01). Similarly, biglycan expression was increased by 3.71-fold (P<0.01). IL-1 and TNF- expression preceded WISP-1 expression in vivo, and stimulated WISP-1 expression in neonatal rat ventricular myocytes in vitro. WISP-1 induced cardiomyocyte hypertrophy was evidenced by increased protein (2.78-fold), but not DNA synthesis, and enhanced Akt phosphorylation and activity. Treatment of primary CF with WISP-1 significantly stimulated proliferation at 48 h (6966±264 vs 5476±307 cells/well, P<0.01) and enhanced collagen release by 72 h (18.4±3.1 vs 8.4±1.0 ng/cell, P<0.01). Our results demonstrate for the first time that WISP-1 and biglycan are upregulated in the non-infarcted myocardium in vivo, suggesting a positive amplification of WISP-1 signaling. WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression in vitro. These results suggest that WISP-1 may play a critical role in post-MI remodeling.