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Cardiovasc Res. 2014 Jun 1;102(3):407-17. doi: 10.1093/cvr/cvu053. Epub 2014 Mar 17.

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

Author information

1
Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
2
Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada Department of Surgery, Hospital for Sick Children, Labatt Family Heart Center, University of Toronto, Toronto, ON, Canada.
3
Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2 boris.hinz@utoronto.ca.

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-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.

KEYWORDS:

Cardiac fibrosis; Cardiac repair; Mechanical stress; Myofibroblast

PMID:
24639195
PMCID:
PMC4030512
DOI:
10.1093/cvr/cvu053
[Indexed for MEDLINE]
Free PMC Article

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