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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cardiovasc+Res 2014 ; 102 (3): 407-17 Nephropedia Template TP
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Integrins ?v?5 and ?v?3 promote latent TGF-?1 activation by human cardiac fibroblast contraction #MMPMID24639195
Sarrazy V; Koehler A; Chow ML; Zimina E; Li CX; Kato H; Caldarone CA; Hinz B
Cardiovasc Res 2014[Jun]; 102 (3): 407-17 PMID24639195show ga
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.