Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction.

Pathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-beta 1 (TGF-beta 1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-beta 1 by inducing a conformational change in the latent complex. The mesenchymal integrins alpha v beta 5 and alpha v beta 3 are expressed in the heart, but their role in the activation of TGF-beta 1 remains elusive. Here, we test whether targeting alpha v beta 5 and alpha v beta 3 integrins reduces latent TGF-beta 1 activation by cardiac fibroblasts with the goal to prevent the formation of alpha-smooth muscle actin (alpha-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis. Using a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins alpha v beta 5 and alpha v beta 3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-beta 1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-beta 1 activation by cardiac fibroblast contraction and loss of alpha-SMA expression, which is restored by adding active TGF-beta 1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-beta 1 activation and induction of alpha-SMA expression. Integrins alpha v beta 5 and alpha v beta 3 both control myofibroblast differentiation by activating latent TGF-beta 1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-beta 1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.