Integrins in cardiac fibrosis

Cells sense mechanical stress and changes in their matrix environment through the integrins, a family of het-erodimeric surface receptors that bind to extracellular matrix ligands and trigger cytoskeletal remodeling, while transducing a wide range of intracellular signals. Integrins have been extensively implicated in regulation of inflammation, repair and fibrosis in many different tissues. This review manuscript discusses the role of integrin-mediated cascades in myocardial fibrosis. In vitro studies have demonstrated that 81 and alpha v integrins play an important role in fibrogenic conversion of cardiac fibroblast, acting through direct stimulation of FAK/Src cascades, or via accentuation of growth factor signaling. Fibrogenic actions of alpha v integrins may be mediated, at least in part, through pericellular activation of latent TGF-8 stores. In vivo evidence supporting the role of integrin heterodimers in fibrotic cardiac remodeling is limited to associative evidence, and to experiments using pharmacologic inhibitors, or global loss-of-function approaches. Studies documenting in vivo actions of integrins on fibroblasts using cell-specific strategies are lacking. Integrin effects on leukocytes may also contribute to the pathogenesis of fibrotic myocardial responses by mediating recruitment and activation of fibrogenic macro-phages. The profile and role of integrins in cardiac fibrosis may be dependent on the underlying pathologic condition. Considering their cell surface localization and the availability of small molecule inhibitors, integrins may be attractive therapeutic targets for patients with heart failure associated with prominent fibrotic remodeling.