%0 Journal Article
%T ¦Â3 Integrin in Cardiac Fibroblast Is Critical for Extracellular Matrix Accumulation during Pressure Overload Hypertrophy in Mouse
%A Sundaravadivel Balasubramanian
%A Lakeya Quinones
%A Harinath Kasiganesan
%A Yuhua Zhang
%A Dorea L. Pleasant
%A Kamala P. Sundararaj
%A Michael R. Zile
%A Amy D. Bradshaw
%A Dhandapani Kuppuswamy
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0045076
%X The adhesion receptor ¦Â3 integrin regulates diverse cellular functions in various tissues. As ¦Â3 integrin has been implicated in extracellular matrix (ECM) remodeling, we sought to explore the role of ¦Â3 integrin in cardiac fibrosis by using wild type (WT) and ¦Â3 integrin null (¦Â3£¿/£¿) mice for in vivo pressure overload (PO) and in vitro primary cardiac fibroblast phenotypic studies. Compared to WT mice, ¦Â3£¿/£¿ 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 ¦Â3£¿/£¿ 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 ¦Â3£¿/£¿ mice was due to compromised cardiac fibroblast function, we analyzed primary cardiac fibroblasts from WT and ¦Â3£¿/£¿ 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 ¦Â3£¿/£¿ 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 ¦Â3£¿/£¿ cells. Adenoviral expression of a dominant negative form of Pyk2 (Y402F) resulted in reduced accumulation of fibronectin. These results indicate that ¦Â3 integrin-mediated Pyk2 signaling in cardiac fibroblasts plays a critical role in PO-induced cardiac fibrosis.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045076