Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction
| Autor: | Anne Koehler, Elena Zimina, Melissa L. Chow, Boris Hinz, Vincent Sarrazy, Hideyuki Kato, Christopher A. Caldarone, Chen Li |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Pathology medicine.medical_specialty Swine Physiology Cardiac fibrosis Integrin Biology Transforming Growth Factor beta1 Extracellular matrix Myofibroblast contraction Fibrosis Physiology (medical) medicine Animals Humans Receptors Vitronectin Myofibroblasts Cells Cultured Integrin alphaVbeta3 Myocardium Cell Differentiation Original Articles medicine.disease Actins Cell biology biology.protein Cardiology and Cardiovascular Medicine Myofibroblast Transforming growth factor |
| Zdroj: | Cardiovascular Research. 102:407-417 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | 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-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 activation of TGF-β1 remains elusive. Here, we test whether targeting αvβ5 and αvβ3 integrins reduces latent TGF-β1 activation by cardiac fibroblasts with the goal to prevent the formation of α-smooth muscle actin (α-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 αvβ5 and αvβ3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-β1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-β1 activation by cardiac fibroblast contraction and loss of α-SMA expression, which is restored by adding active TGF-β1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-β1 activation and induction of α-SMA expression. Conclusions Integrins αvβ5 and αvβ3 both control myofibroblast differentiation by activating latent TGF-β1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-β1 activation by cardiac myofibroblasts and progression of fibrosis in the heart. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|