Antagonism of Angiotensin II AT1 Receptor and Silencing of CD44 Gene Expression Inhibit Cardiac Fibroblast Activation via Modulating TGF-<i>β</i>1/Smad Signaling Pathway

Angiotensin II (Ang II) is known to elicit cardiac\r\nfibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular\r\nmechanisms underlying cardiac fibrosis are still not well understood. This\r\nstudy examines the roles of the AT1 receptor and CD44 gene expression in\r\ncollagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts\r\nwere isolated from the neonatal rat hearts; the activation of fibroblasts was evaluated using\r\nthe assays of cell viability and migration, and silencing of CD44 gene\r\nexpression was conducted with small interfering RNA\r\n(siRNA). Results showed that Ang II significantly increases the cell\r\nproliferation and migration in a dose-dependent manner. Upon\r\nactivation, the protein levels of TGF-β1,\r\nSmad2, Smad4 and collagen I were significantly increased (all p by the AT1 receptor\r\nblocker, telmisartan (all p β1\r\nas demonstrated by Pearson correlation analysis (r = 0.955, p \u003c 0.01). Gene\r\ntransfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of\r\nCD44 mRNA and protein, significantly reduced the production of collagen I. In\r\nsummary, these results indicate that the proliferation, migration and collagen\r\nproduction from Ang II activated cardiac fibroblasts are potentially mediated\r\nby the AT1 receptor and CD44. Such a signaling mechanism could be crucial for\r\nthe production of collagen and the development of tissue fibrosis in the heart.