title: WISP1, a pro-mitogenic, pro-survival factor, mediates tumor necrosis factor-alpha (TNF-alpha)-stimulated cardiac fibroblast proliferation but inhibits TNF-alpha-induced cardiomyocyte death.
abstract: 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-alpha (TNF-alpha). Here we investigated (i) the localization of TNF-alpha and WISP1 in post-infarct heart, (ii) the mechanism of TNF-alpha-mediated WISP1 induction in primary human cardiac fibroblasts (CF), (iii) the role of WISP1 in TNF-alpha-mediated CF proliferation and collagen production, and (iv) the effects of WISP1 on TNF-alpha-mediated cardiomyocyte death. TNF-alpha and WISP1 expressions were increased in the border zones and non-ischemic remote regions of the post-ischemic heart. In CF, TNF-alpha potently induced WISP1 expression in cyclic AMP response element-binding protein (CREB)-dependent manner. TNF-alpha induced CREB phosphorylation in vitro and DNA binding and reporter gene activities in vivo. TNF-alpha induced CREB activation via ERK1/2, and inhibition of ERK1/2 and CREB blunted TNF-alpha-mediated WISP1 induction. Most importantly, WISP1 knockdown attenuated TNF-alpha stimulated collagen production and CF proliferation. Furthermore, WISP1 attenuated TNF-alpha-mediated cardiomyocyte death, thus demonstrating pro-mitogenic and pro-survival effects for WISP1 in myocardial constituent cells. Our results suggest that a TNF-alpha/WISP1 signaling pathway may contribute to post-infarct cardiac remodeling, a condition characterized by fibrosis and progressive cardiomyocyte loss.
authors.affiliation: Department of Veterans Affairs, South Texas Veterans Health Care System, TX 78229, USA.
authors.forename: Kaliyamurthi
authors.initials: K
authors.lastname: Venkatachalam
authors.forename: Balachandar
authors.initials: B
authors.lastname: Venkatesan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Peter C
authors.initials: PC
authors.lastname: Melby
authors.forename: Sailesh
authors.initials: S
authors.lastname: Nandish
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
authors.forename: Robert A
authors.initials: RA
authors.lastname: Clark
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar