The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis

Abstract

The extracellular matrix (ECM) provides structural support and a microenvironmentfor soluble extracellular molecules. ECM is comprised of numerous proteins which can be broadly classified as fibrillar (collagen types I and III) and non-fibrillar (basement membrane, proteoglycans, and glycoproteins). The basement membrane provides an interface between the cardiomyocytes and the fibrillar ECM, while proteoglycans sequester soluble growth factors and cytokines. Myocardial fibrosis was originally only linked to accumulation of fibrillar collagens, but is now recognized as the expansion of the ECM including the non-fibrillar ECM proteins. Myocardial fibrosis can be reparative to replace the lost myocardium (e.g., ischemic injury or myocardial infarction), or can be reactive resulting from pathological activity of fibroblasts (e.g., dilated or hypertrophic cardiomyopathy). Contribution of fibrillar collagens to fibrosis is well studied, but the role of the non-fibrillar ECM proteins has remained less explored. In this article, we provide an overview of the contribution of the non-fibrillar components of the extracellular space of the heart to highlight the potential significance of these molecules in fibrosis, with direct evidence for some, although not all of these molecules in their direct contribution to fibrosis.

Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response

“…The ECM constitutes a complex network of fibrillary (fibrillar collagens) and non-fibrillary (composed by the basement membrane, proteoglycans, and glycoproteins) components within the extracellular space that have both signaling and structural functions ( Chute et al, 2019 ). New proteomic approaches have revealed that 90% of cardiac ECM is composed of 10 different proteins, from which serum albumin, collagens (collagens I, III, and IV), non-collagenous glycoproteins [fibronectin (FN) and laminin], proteoglycans, glucosaminoglycans (GAGs), and elastins are the most common ( Lindsey et al, 2018 ).…”

Beneficial Effects of Mineralocorticoid Receptor Antagonism on Myocardial Fibrosis in an Experimental Model of the Myxomatous Degeneration of the Mitral Valve

“…Our study provides information about the role of the non-fibrillar proteins in myocardial fibrosis. The extracellular proteoglycans such as aggrecan, the small leucine-rich proteoglycans, including decorin and lumican, and the cell surface proteoglycan syndecan-4 [ 10 , 30 ] were the principal proteoglycans altered in cardiac fibrosis associated with mitral valve fibromyxomatous degeneration that could lead to MVP. The extracellular proteoglycans are the main proteoglycans involved in the stabilization of the ECM and collagen synthesis [ 10 ].…”

“…The extracellular proteoglycans such as aggrecan, the small leucine-rich proteoglycans, including decorin and lumican, and the cell surface proteoglycan syndecan-4 [ 10 , 30 ] were the principal proteoglycans altered in cardiac fibrosis associated with mitral valve fibromyxomatous degeneration that could lead to MVP. The extracellular proteoglycans are the main proteoglycans involved in the stabilization of the ECM and collagen synthesis [ 10 ]. Decorin and lumican are increased in myocardial fibrosis following pressure overload or myocardial infarction [ 31 ], while syndecan-4 contributes to myofibroblast differentiation in these settings [ 32 ].…”

“…ECM is composed by fibrillar proteins (such as collagen), and other non-fibrillar proteins (including fibronectin, proteoglycans, glycoproteins or glycosaminoglycans). The accumulation of both fibrillar and non-fibrillar proteins contributes to cardiac fibrosis [ 10 ]. One of the most studied fibrogenic axis is the Aldosterone/mineralocorticoid receptor (MR) pathway.…”

Role of melatonin in the angiogenesis potential; highlights on the cardiovascular disease

“…MI is touted as the most common cause of human death worldwide correlated with partial or complete occlusion of microvasculature in the affected areas [8]. In most MI patients, the lack of sufficient blood supplementation to the infarcted area leads to extensive necrosis and aberrant ECM remodeling [9]. Restorative compensatory mechanisms and promotion of fibroblasts in MI patients contribute to the bulk secretion of type I collagen in the interstitial spaces, leading to insufficient myocardial tissue and diastolic dysfunction [10].…”