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Abstract
BackgroundTo 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.MethodsStaining 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.ResultsSHR 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.ConclusionInhibition 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.
Highlights
To date the transforming growth factor-β1 (TGF-β1) activation mediated by integrin ανβ5 during fibrosis is well-known
Hypertensive rat hearts show higher fibrosis and TGF‐β1 expression than normotensive controls It is well known that a common feature of hypertension is left ventricular hypertrophy (LVH), mainly characterized by the cardiac tissue remodelling, in which TGF-β1 plays a major role as molecular mediator of extracellular matrix (ECM) alterations [2, 27]
In this study we found a direct effect of hypertension on integrin-mediated TGF-β1 activation and, by in vitro experiments, the positive effects of cilengitide treatment in decreasing the fibrosis progression by integrin ανβ5 inhibition
Summary
To date the TGF-β1 activation mediated by integrin ανβ during fibrosis is well-known This process has been shown in the heart, where cardiac fibroblasts (CF) differentiate into α-smooth muscle actin (α-SMA)-positive myofibroblasts (MyoFB). The TGF-β1 activation models are numerous, among these the integrin-mediated mechanotransduction of TGF-β1 release from its latent complex in ECM is gaining in last years a strong relief [8, 9]. This model has been primarily described starting from studies on lung and skin fibrotic disease [10,11,12]. It has been reported in these pathologies that several integrins are able to bind the ECM component of TGFβ1 latent complex and to release TGF-β1 by mechanical stretching [13,14,15,16]
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