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Review
. 2017 May 1;127(5):1600-1612.
doi: 10.1172/JCI87491. Epub 2017 May 1.

The extracellular matrix in myocardial injury, repair, and remodeling

Nikolaos G Frangogiannis
Review

The extracellular matrix in myocardial injury, repair, and remodeling

Nikolaos G Frangogiannis. J Clin Invest. .

Abstract

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.

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Conflict of interest statement

Conflict of interest: The author has declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. The ECM during the inflammatory phase of cardiac repair.
(A) Cardiomyocyte necrosis is associated with induction and activation of proteases in the infarcted region. Activated proteases cause fragmentation of the native ECM, resulting in release of matrikines, bioactive peptides that activate an inflammatory macrophage phenotype and may also modulate responses of fibroblasts and vascular endothelial cells. The effects of MMPs in the ischemic and infarcted myocardium are not limited to the ECM. MMPs may modulate inflammatory and reparative responses by processing cytokines and chemokines. They may also inhibit chemokine actions by degrading glycosaminoglycan-binding sites and mediate dysfunction by targeting intracellular proteins. Increased vessel permeability in the infarcted region results in extravasation of plasma proteins, such as fibrinogen and fibronectin. Accumulation of these proteins in the infarcted region forms a provisional matrix that serves as a scaffold for infiltrating leukocytes. Fibrin and fibronectin modulate the phenotype of immune and reparative cells through integrin-mediated actions. (B) Fibrinogen/fibrin staining using a peroxidase-based technique (black) illustrates the formation of the provisional fibrin-based matrix network (indicated by arrows) in the infarcted canine myocardium (one hour ischemia followed by seven days reperfusion). Counterstained with eosin. Scale bar: 50 μm. Reproduced with permission from the FASEB Journal (155).
Figure 2
Figure 2. The role of the cell-derived provisional matrix in cardiac repair.
(A) During the proliferative phase of cardiac repair, fibroblasts and macrophages contribute to the formation of a cell-derived provisional matrix, enriched with a wide range of matricellular macromolecules that do not serve a primary structural role, but modulate cellular phenotype and function. Specialized matrix proteins (such as ED-A domain fibronectin) and matricellular proteins, such as TSPs, tenascin-C (TNC), osteopontin (OPN), SPARC, periostin, osteoglycin, and members of the CCN family, bind to the matrix and modulate growth factor and protease activity. Specific matricellular proteins have been reported as regulating inflammation, participating in fibrogenic and angiogenic responses, modulating cardiomyocyte survival, and contributing to assembly of the structural matrix. (B) Matricellular proteins may be critical in spatial and temporal regulation of growth factor signaling. Immunohistochemical staining using a peroxidase-based technique (black) shows the strikingly selective localization of the prototypical matricellular protein TSP1 (arrows), a critical activator of TGF-β, in the border zone of a healing canine myocardial infarction (one hour ischemia followed by seven days reperfusion). Spatially and temporally restricted induction of matricellular proteins regulates growth factor signaling, preventing expansion of profibrotic responses beyond the infarcted area, despite possible diffusion of the soluble mediators in viable segments. Counterstained with eosin. Reproduced with permission from Circulation (75). Scale bar: 50 μm. GAGs, glycosaminoglycosans.
Figure 3
Figure 3. Matricellular proteins regulate cellular responses in the pressure-overloaded myocardium.
In the pressure-overloaded heart, mechanical stress activates neurohumoral pathways and induces synthesis and release of matricellular macromolecules, including TSP1, -2, and -4, tenascin-C, OPN, SPARC, and periostin. Matricellular proteins have been implicated in regulation of matrix assembly, in transduction of mechanosensitive signaling, and in the pathogenesis of fibrosis and cardiac hypertrophy, and may also modulate survival of cardiomyocytes under conditions of stress. The effects of the matricellular proteins are exerted through direct activation of cell surface receptors or through modulation of growth factor– and protease-mediated responses.
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