Dataset Information
Integrins ?v?5 and ?v?3 promote latent TGF-?1 activation by human cardiac fibroblast contraction.
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ABSTRACT: Aims
Pathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-?1 (TGF-?1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-?1 by inducing a conformational change in the latent complex. The mesenchymal integrins ?v?5 and ?v?3 are expressed in the heart, but their role in the activation of TGF-?1 remains elusive. Here, we test whether targeting ?v?5 and ?v?3 integrins reduces latent TGF-?1 activation by cardiac fibroblasts with the goal to prevent the formation of ?-smooth muscle actin (?-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis.Methods and results
Using a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins ?v?5 and ?v?3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-?1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-?1 activation by cardiac fibroblast contraction and loss of ?-SMA expression, which is restored by adding active TGF-?1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-?1 activation and induction of ?-SMA expression.Conclusions
Integrins ?v?5 and ?v?3 both control myofibroblast differentiation by activating latent TGF-?1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-?1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.
SUBMITTER: Sarrazy V
PROVIDER: S-EPMC4030512 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction.
Cardiovascular research 20140317 3
<h4>Aims</h4>Pathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-β1 (TGF-β1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-β1 by inducing a conformational change in the latent complex. The mesenchymal integrins αvβ5 and αvβ3 are expressed in the heart, but their role in the act ...[more]