Beta 3 Integrin In Cardiac Fibroblast Is Critical For Extracellular Matrix Accumulation During Pressure Overload Hypertrophy In Mouse
PLOS ONE(2012)
Abstract
The adhesion receptor beta 3 integrin regulates diverse cellular functions in various tissues. As beta 3 integrin has been implicated in extracellular matrix (ECM) remodeling, we sought to explore the role of beta 3 integrin in cardiac fibrosis by using wild type (WT) and b3 integrin null (beta 3-/-) mice for in vivo pressure overload (PO) and in vitro primary cardiac fibroblast phenotypic studies. Compared to WT mice, beta 3-/- mice upon pressure overload hypertrophy for 4 wk by transverse aortic constriction (TAC) showed a substantially reduced accumulation of interstitial fibronectin and collagen. Moreover, pressure overloaded LV from beta 3-/- mice exhibited reduced levels of both fibroblast proliferation and fibroblast-specific protein-1 (FSP1) expression in early time points of PO. To test if the observed impairment of ECM accumulation in beta 3-/- mice was due to compromised cardiac fibroblast function, we analyzed primary cardiac fibroblasts from WT and beta 3-/- mice for adhesion to ECM proteins, cell spreading, proliferation, and migration in response to platelet derived growth factor-BB (PDGF, a growth factor known to promote fibrosis) stimulation. Our results showed that beta 3-/- cardiac fibroblasts exhibited a significant reduction in cell-matrix adhesion, cell spreading, proliferation and migration. In addition, the activation of PDGF receptor associated tyrosine kinase and non-receptor tyrosine kinase Pyk2, upon PDGF stimulation were impaired in beta 3-/- cells. Adenoviral expression of a dominant negative form of Pyk2 (Y402F) resulted in reduced accumulation of fibronectin. These results indicate that beta 3 integrin-mediated Pyk2 signaling in cardiac fibroblasts plays a critical role in PO-induced cardiac fibrosis.
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Key words
cytoskeleton,integrins,actins
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