Abstract 17572: Regulation of Myocardial Collagen Synthesis and Degradation by Beta-Arrestin 1/2 in Maladaptive Ventricular Remodeling
Cardiac fibroblasts (CF) produce and degrade extracellular matrix and are critical in regulating myocardial remodeling which can lead to heart failure. β-arrestins regulate G protein-coupled receptor (GPCR) function and also mediate GPCR-independent signaling. This study investigates the role of β-arrestin signaling in adult human CF isolated from normal and failing left ventricles. β-arrestin-1 expression is increased 1.5-fold in failing CF relative to normal controls. siRNA-mediated knockdown of β-arrestin 1 or 2 in failing CF decreased the expression of α-smooth muscle actin, suggesting that β-arrestins play an important role in the transformation of CF to activated myofibroblasts in the failing ventricle. This effect was more pronounced by decreasing β-arrestin 1 expression. Knockdown of β-arrestin 1 or 2 in failing CF led to increased β-agonist-stimulated cAMP production and restoration of β-agonist-mediated inhibition of collagen synthesis similar to normal CF. This effect was greater with decreased b-arrestin 2 expression. β-arrestin 1 knockdown led to a significant decline in TGF-β-stimulated collagen synthesis in normal and failing CF. This is likely mediated by decreased ERK 1/2 phosphorylation and activation which resulted from β-arrestin 1 knockdown. Interestingly, β-arrestin 2 knockdown did not have this effect, demonstrating specificity for regulating TGF-β-stimulated collagen synthesis. Decreased β-arrestin 1or 2 expression in failing CF also led to a decline in MMP-2 expression and activity which plays a key role in matrix degradation. MMP-2 expression was upregulated 1.5-fold in failing CF. In conclusion, our results suggest that β-arrestins play an important role in the regulation of collagen synthesis and degradation by CF. This occurs through GPCR (β-AR/cAMP) and GPCR-independent (TGF-β/ERK) mechanisms. Inhibition of β-arrestin signaling in CF may represent a novel approach to inhibit or decrease maladaptive cardiac remodeling following myocardial injury.
- © 2012 by American Heart Association, Inc.