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

J. T. Colston, S. D. De La Rosa, M. Koehler, K. Gonzales, R. Mestril, G. L. Freeman, S. R. Bailey, B. Chandrasekar

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

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-1β and TNF-α 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.

Original languageEnglish (US)
Pages (from-to)H1839-H1846
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 2007

Keywords

  • Akt
  • Cardiomyocyte hypertrophy
  • Cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed family
  • Myocardial infarction
  • Myocardial remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Colston, J. T., De La Rosa, S. D., Koehler, M., Gonzales, K., Mestril, R., Freeman, G. L., Bailey, S. R., & Chandrasekar, B. (2007). Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. American Journal of Physiology - Heart and Circulatory Physiology, 293(3), H1839-H1846. https://doi.org/10.1152/ajpheart.00428.2007