2. Academic Validation
  3. Integrin ανβ5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats

Integrin ανβ5 in vitro inhibition limits pro-fibrotic response in cardiac fibroblasts of spontaneously hypertensive rats

  • J Transl Med. 2018 Dec 12;16(1):352. doi: 10.1186/s12967-018-1730-1.
Gianluca Lorenzo Perrucci 1 2,  Veronica Antonietta Barbagallo 3,  Maria Corlianò 3,  Delfina Tosi 4,  Rosaria Santoro 3,  Patrizia Nigro 3,  Paolo Poggio 5,  Gaetano Bulfamante 4,  Federico Lombardi 6 7,  Giulio Pompilio 6 3
Affiliations

Affiliations

  • 1 Unità di Biologia Vascolare e Medicina Rigenerativa, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, via Festa del Perdono 7, Milan, Italy. [email protected].
  • 2 Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino IRCCS, via Carlo Parea 4, Milan, Italy. [email protected].
  • 3 Unità di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino IRCCS, via Carlo Parea 4, Milan, Italy.
  • 4 Unità di Patologia, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Ospedale San Paolo, via Antonio di Rudinì 8, Milan, Italy.
  • 5 Unità per lo Studio di Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, via Carlo Parea 4, Milan, Italy.
  • 6 Unità di Biologia Vascolare e Medicina Rigenerativa, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, via Festa del Perdono 7, Milan, Italy.
  • 7 Unità di Cardiologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, Milan, Italy.
PMID: 30541573 DOI: 10.1186/s12967-018-1730-1
Abstract

Background: To date the TGF-β1 activation mediated by Integrin ανβ5 during fibrosis is well-known. This process has been shown also in the heart, where cardiac fibroblasts (CF) differentiate into α-smooth muscle actin (α-SMA)-positive myofibroblasts (MyoFB). Here, we studied the effects on CF, isolated by spontaneously hypertensive rats (SHR), of Integrin ανβ5 inhibition in MyoFB differentiation.

Methods: Staining and immunohistochemistry were performed on rat cardiac tissue. CF were isolated by enzymatic digestion from SHR (SHR-CF) and normotensive WKY (WKY-CF) rat hearts and then treated for in vitro evaluation.

Results: SHR heart tissues revealed a higher TGF-β1 expression vs. WKY samples. SHR-CF showed an enhanced SMAD2/3 activation and an up-regulated expression of α-SMA, a typical MyoFB marker, especially after TGF-β1 treatment. Immunostaining on cardiac tissues revealed a higher expression of Integrin ανβ5 in SHR vs. WKY rat hearts. In vitro results confirmed the up-regulation of Integrin ανβ5 expression in SHR-CF at basal condition and after TGF-β1 treatment, in comparison with WKY-CF. Inhibition of Integrin ανβ5 by cilengitide treatment led a decreased expression of ανβ5, collagen I, and α-SMA in SHR-CF vs. WKY-CF, resulting in a diminished differentiation of CF into MyoFB. Taking together, results suggested that SHR-CF are more susceptible to TGF-β1, showing an up-regulated activation of SMAD2/3 signaling, and an increased ανβ5, α-SMA, and collagen I expression. Hypertension stimulus promoted an up-regulation of Integrin ανβ5 on SHR cardiac tissue and its in vitro inhibition reverted pro-fibrotic events of SHR-CF.

Conclusion: Inhibition of Integrin ανβ5 exerted by cilengitide strongly diminished SHR-CF differentiation into detrimental MyoFB. So, Integrin ανβ5 might be considered a novel therapeutic target and cilengitide an effective pharmacological tool to limit the progression of hypertension-induced cardiac fibrosis.

Keywords

Cilengitide; Hypertension; Integrin ανβ5; Myofibroblast; TGF-β1.

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