title: Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sarrazy
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
authors.forename: Anne
authors.initials: A
authors.lastname: Koehler
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Chow
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
authors.forename: Elena
authors.initials: E
authors.lastname: Zimina
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
authors.forename: Chen X
authors.initials: CX
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: 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.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Caldarone
authors.affiliation: 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.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000199:Actins / Q000032:analysis; D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000473:pathology; D058628:Myofibroblasts / Q000473:pathology*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; D053773:Transforming Growth Factor beta1; C064660:integrin alphaVbeta5
keywords: Cardiac fibrosis; Cardiac repair; Mechanical stress; Myofibroblast