Matricellular Proteins in Cardiac Adaptation and Disease

Abstract

<jats:p>The term matricellular proteins describes a family of structurally unrelated extracellular macromolecules that, unlike structural matrix proteins, do not play a primary role in tissue architecture, but are induced following injury and modulate cell-cell and cell-matrix interactions. When released to the matrix, matricellular proteins associate with growth factors, cytokines, and other bioactive effectors and bind to cell surface receptors transducing signaling cascades. Matricellular proteins are upregulated in the injured and remodeling heart and play an important role in regulation of inflammatory, reparative, fibrotic and angiogenic pathways. Thrombospondin (TSP)-1, -2, and -4 as well as tenascin-C and -X secreted protein acidic and rich in cysteine (SPARC), osteopontin, periostin, and members of the CCN family (including CCN1 and CCN2/connective tissue growth factor) are involved in a variety of cardiac pathophysiological conditions, including myocardial infarction, cardiac hypertrophy and fibrosis, aging-associated myocardial remodeling, myocarditis, diabetic cardiomyopathy, and valvular disease. This review discusses the properties and characteristics of the matricellular proteins and presents our current knowledge on their role in cardiac adaptation and disease. Understanding the role of matricellular proteins in myocardial pathophysiology and identification of the functional domains responsible for their actions may lead to design of peptides with therapeutic potential for patients with heart disease.</jats:p>

The extracellular matrix in myocardial injury, repair, and remodeling

“…SPARC has been shown to protect from cardiac rupture and postinfarction heart failure by contributing to collagen maturation through activation of growth factor signaling (80). Periostin serves as a crucial regulator of fibroblast matrix is followed by secretion of cellular fibronectin by fibroblasts and macrophages (62,63) and by deposition of hyaluronan and versican, forming a network of cell-derived provisional matrix that is later enriched with a wide range of matricellular macromolecules (12). During the proliferative phase of healing, the highly dynamic matrix becomes a regulatory center that transduces essential signals to activate reparative fibroblasts and vascular cells.…”

“…Distinct actions of matricellular protein fragments further complicate therapeutic implementation. Identification of the functional domains responsible for specific protective or detrimental matricellular actions is needed in order to design peptide-based strategies that simulate these effects (12,135).…”

“…Because of its importance in preserving structural integrity and function of the heart (127) and its crucial involvement in regulation of cellular responses in cardiac injury, repair, and remodeling (12), the cardiac ECM provides unique opportunities for therapeutic interventions in patients with myocardial infarction and heart failure. Several therapeutic approaches with established beneficial effects in patients with myocardial infarction and heart failure, such as ACE inhibition, angiotensin type 1 receptor blockade, β-adrenergic receptor antagonism, and mechanical unloading, may exert some of their protective actions through modulation of ECM deposition and metabolism (128).…”

“…Specialized matrix proteins and matricellular macromolecules critically modulate the cellular responses in the infarcted and remodeling heart and may hold the key for development of new effective strategies to optimize repair and to reduce adverse remodeling following cardiac injury. Animal model studies have suggested that several members of the matricellular family protect the infarcted heart from adverse remodeling (12). Therapeutic approaches based on matricellular proteins are particularly attractive because of the capacity electrical activity.…”

Congenital Heart Disease: In Search of Remedial Etiologies

“…Already much is being learned about their potential for repair through homotypic interactions or heterotypic interactions with myocytes. Modes of contact between fibroblasts or fibroblasts and myocytes include connexin-based, gap junctions through which ions or small molecules (microRNAs) can be transferred [42], tunneling nanotubes [43] through which mitochondria can be exchanged, or by paracrine secretions of cytokines, growth factors, or matricellular proteins that facilitate their engraftment, proliferation, and/or differentiation [44].…”