WNT1-inducible signaling pathway protein-1 (WISP1), a member of the CYR61/CTGF/Nov family of growth factors, can mediate cell growth, transformation, and survival. Previously we demonstrated that WISP1 is up-regulated in post-infarct heart, stimulates cardiac fibroblast proliferation, and is induced by the proinflammatory cytokine tumor necrosis factor-a (TNF-a). Here we investigated (i) the localization of TNF-a and WISP1 in post-infarct heart, (ii) the mechanism of TNF-a-mediated WISP1 induction in primary human cardiac fibroblasts (CF), (iii) the role of WISP1 in TNF-a-mediated CF proliferation and collagen production, and (iv) the effects of WISP1 on TNF-a-mediated cardiomyocyte death. TNF-a and WISP1 expressions were increased in the border zones and non-ischemic remote regions of the post-ischemic heart. In CF, TNF-a potently induced WISP1 expression in cyclic AMP response element-binding protein (CREB)-dependent manner. TNF-a induced CREB phosphorylation in vitro and DNA binding and reporter gene activities in vivo. TNF-a induced CREB activation via ERK1/2, and inhibition of ERK1/2 and CREB blunted TNF-a-mediated WISP1 induction. Most importantly, WISP1 knockdown attenuated TNF-a stimulated collagen production and CF proliferation. Furthermore, WISP1 attenuated TNF-a-mediated cardiomyocyte death, thus demonstrating pro-mitogenic and pro-survival effects for WISP1 in myocardial constituent cells. Our results suggest that a TNF-a/WISP1 signaling pathway may contribute to post-infarct cardiac remodeling, a condition characterized by fibrosis and progressive cardiomyocyte loss.

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