Abstract 549: Wnt-Induced Secreted Protein-1 is a Pro-Hypertrophic and Pro-Fibrotic Growth Factor
Background: Remodeling following myocardial infarction (MI) involves structural changes in the heart characterized by myocyte hypertrophy, fibroblast proliferation, and extracellular matrix deposition. WISP-1 (Wnt-induced secreted protein-1) is a member of the CCN family, 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, collagen expression, and ROS generation.
Methods: Male C57Bl/6 mice (25 g) underwent permanent occlusion of the LAD coronary artery. Sham-operated mice served as controls. WISP-1 expression was analyzed by Northern and Western blot. Myocyte hypertrophy was measured by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, soluble collagen release by Sircol assay, and ROS generation using dichlorofluorescein-loaded CF.
Results: 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). A significant increase in fibrosis was detected at 1 week (picrosirus staining). Under in vitro conditions, WISP-1 induced primary cardiomyocyte hypertrophy as evidenced by increased protein (2.78-fold), but not DNA synthesis. Treatment of primary CF with WISP-1 significantly increased ROS generation at 1 hr (155.5±15 vs 128.9±13.4 mF.U./min/cell count, P<0.01), stimulated proliferation at 48 hrs (6966±264 vs. 5476±307 cells/well, P<0.01) and enhanced collagen synthesis by 72 hrs (18.4±3.1 vs. 8.4±1.0 ng/cell, P<0.01) compared to vehicle treated controls.
Conclusions: Our results demonstrate for the first time that WISP-1 is expressed in vivo in the noninfarcted myocardium following permanent LAD occlusion. In vitro, WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression. Since, WISP-1 stimulates ROS generation, our results suggest that WISP-1 may signal in an ROS-dependent manner. Since WISP-1 stimulates myocyte hypertrophy, fibroblast proliferation, and ECM expression, our results suggest that WISP-1 may play an important role in post-MI remodeling.