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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1839    most recent 00428.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Colston, J. T. Articles by Chandrasekar, B. Search for Related Content PubMed PubMed Citation Articles by Colston, J. T. Articles by Chandrasekar, B.

Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor

¹Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ²Department of Physiology and Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois; and ³South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Texas

Submitted 6 April 2007 ; accepted in final form 4 July 2007

Wnt1-induced secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (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 postinfarct myocardium and whether WISP-1 exerts prohypertrophic and mitogenic effects stimulating myocyte hypertrophy, cardiac fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25 g) mice underwent permanent occlusion of the left anterior descending coronary artery. mRNA and protein levels were analyzed by Northern and Western blot analyses. 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 noninfarct zone of the left ventricle, 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 (6,966 ± 264 vs. 5,476 ± 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 noninfarcted 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-myocardial infarction remodeling.

cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed family; myocardial infarction; myocardial remodeling; Akt; cardiomyocyte hypertrophy

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