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

Waled A Shihata,Jaye P F Chin-Dusting,Mohammad R A Putra

doi:10.3389/fphar.2017.00567

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.

Highlights

Fibrosis, a process of wound reparation, is a cellular response to tissue damage or insult, preceded by an inflammatory response
Cav-1 negatively regulates Smad signaling by binding the caveolin scaffolding domain (CSD) component, the key functional component of Cav-1, to TGF-β type I receptor (TβRI), which in turn diminishes the downstream signaling of Smads via the transforming growth factor β (TGF-β) receptors (Razani et al, 2001b)
This study observed that silencing Cav-1 gene via small interfering RNA or via knockdown model leads to inhibited angiotensin II (AngII) activation, suggesting that epidermal growth factor receptor (EGFR) association with Cav-1 leads to prolonged activation (Chen et al, 2012)

Summary

INTRODUCTION

A process of wound reparation, is a cellular response to tissue damage or insult, preceded by an inflammatory response. The repair process progresses with the replacement of connective tissue or fibrous tissue-producing mesenchymal cells such as fibroblasts, the primary cells involved in fibrosis The onset of fibrosis begins with epithelial or endothelial activation, which results in the release of inflammatory mediators, for both clot formation (hemostasis) and inflammatory cell recruitment. Innate immune cells, such as neutrophils, release pro-fibrotic factors or cytokines, including matrix metalloproteinases (MMPs), elastases, and cathepsins, to cleave connective tissue and in turn disrupt the basement membrane, promoting cell migratory capacities (Wynn, 2007; Wick et al, 2013). Caveolin-1 (Cav-1), originally called vesicular integral membrane protein of 21 kD (VIP-21), is generally accepted as the predominant protein involved in caveolae’s key regulatory function in intracellular signaling pathways evident in fibrotic processes observed in different organs including cardiac, lung, and kidney fibrosis (Drab et al, 2001)

CARDIAC FIBROSIS

LUNG FIBROSIS

PERITONEAL AND KIDNEY FIBROSIS

LIVER FIBROSIS

Findings

CONCLUSION