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      Is There a Potential Therapeutic Role for Caveolin-1 in Fibrosis?

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          Abstract

          Fibrosis is a process of dysfunctional wound repair, described by a failure of tissue regeneration and excessive deposition of extracellular matrix, resulting in tissue scarring and subsequent organ deterioration. There are a broad range of stimuli that may trigger, and exacerbate the process of fibrosis, which can contribute to the growing rates of morbidity and mortality. Whilst the process of fibrosis is widely described and understood, there are no current standard treatments that can reduce or reverse the process effectively, likely due to the continuing knowledge gaps surrounding the cellular mechanisms involved. Several cellular targets have been implicated in the regulation of the fibrotic process including membrane domains, ion channels and more recently mechanosensors, specifically caveolae, particularly since these latter contain various signaling components, such as members of the TGFβ and MAPK/ERK signaling pathways, all of which are key players in the process of fibrosis. This review explores the anti-fibrotic influences of the caveola, and in particular the key underpinning protein, caveolin-1, and its potential as a novel therapeutic target.

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          Most cited references65

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          Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.

          Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.
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            Cells respond to mechanical stress by rapid disassembly of caveolae.

            The functions of caveolae, the characteristic plasma membrane invaginations, remain debated. Their abundance in cells experiencing mechanical stress led us to investigate their role in membrane-mediated mechanical response. Acute mechanical stress induced by osmotic swelling or by uniaxial stretching results in a rapid disappearance of caveolae, in a reduced caveolin/Cavin1 interaction, and in an increase of free caveolins at the plasma membrane. Tether-pulling force measurements in cells and in plasma membrane spheres demonstrate that caveola flattening and disassembly is the primary actin- and ATP-independent cell response that buffers membrane tension surges during mechanical stress. Conversely, stress release leads to complete caveola reassembly in an actin- and ATP-dependent process. The absence of a functional caveola reservoir in myotubes from muscular dystrophic patients enhanced membrane fragility under mechanical stress. Our findings support a new role for caveolae as a physiological membrane reservoir that quickly accommodates sudden and acute mechanical stresses. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover.

              Endocytosis of cell surface receptors is an important regulatory event in signal transduction. The transforming growth factor beta (TGF-beta) superfamily signals to the Smad pathway through heteromeric Ser-Thr kinase receptors that are rapidly internalized and then downregulated in a ubiquitin-dependent manner. Here we demonstrate that TGF-beta receptors internalize into both caveolin- and EEA1-positive vesicles and reside in both lipid raft and non-raft membrane domains. Clathrin-dependent internalization into the EEA1-positive endosome, where the Smad2 anchor SARA is enriched, promotes TGF-beta signalling. In contrast, the lipid raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover. Thus, segregation of TGF-beta receptors into distinct endocytic compartments regulates Smad activation and receptor turnover.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 August 2017
                2017
                : 8
                : 567
                Affiliations
                [1] 1Vascular Pharmacology Laboratory, Cardiovascular Disease Program, Department of Pharmacology, Biomedical Discovery Institute, Monash University Clayton, VIC, Australia
                [2] 2Department of Medicine, Monash University Clayton, VIC, Australia
                [3] 3Baker Heart and Diabetes Institute Melbourne, VIC, Australia
                Author notes

                Edited by: Pedro D'Orléans-Juste, Université de Sherbrooke, Canada

                Reviewed by: Beate Rassler, Leipzig University, Germany; Joan Krepinsky, McMaster University, Canada; Yan Sanders, University of Alabama at Birmingham, United States

                *Correspondence: Waled A. Shihata waled.shihata@ 123456monash.edu

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2017.00567
                5609631
                28970796
                5e8da05a-34e8-475b-8aab-6b4b89ecaea6
                Copyright © 2017 Shihata, Putra and Chin-Dusting.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 April 2017
                : 09 August 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 79, Pages: 8, Words: 6650
                Categories
                Pharmacology
                Mini Review

                Pharmacology & Pharmaceutical medicine
                caveolae,caveolin-1,cardiac fibrosis,lung fibrosis,kidney fibrosis

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