Review article
The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction

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Abstract

The dynamic alterations in the cardiac extracellular matrix following myocardial infarction not only determine the mechanical properties of the infarcted heart, but also directly modulate the inflammatory and reparative response. During the inflammatory phase of healing, rapid activation of Matrix Metalloproteinases (MMP) causes degradation of the cardiac extracellular matrix. Matrix fragments exert potent pro-inflammatory actions, while MMPs process cytokines and chemokines altering their biological activity. In addition, vascular hyperpermeability results in extravasation of fibronectin and fibrinogen leading to formation of a plasma-derived provisional matrix that serves as a scaffold for leukocyte infiltration. Clearance of the infarct from dead cells and matrix debris is essential for resolution of inflammation and marks the transition to the proliferative phase. The fibrin-based provisional matrix is lysed and cellular fibronectin is secreted. ED-A fibronectin, mechanical tension and Transforming Growth Factor (TGF)-β are essential for modulation of fibroblasts into myofibroblasts, the main collagen-secreting cells in the wound. The matricellular proteins thrombospondin-1 and -2, osteopontin, tenascin-C, periostin, and secreted protein acidic and rich in cysteine (SPARC) are induced in the infarct regulating cellular interactions and promoting matrix organization. As the infarct matures, matrix cross-linking results in formation of a dense collagen-based scar. At this stage, shielding of fibroblasts from external mechanical tension by the mature matrix network may promote deactivation and cellular quiescence. The components of the extracellular matrix do not passively follow the pathologic alterations of the infarcted heart but critically modulate inflammatory and reparative pathways by transducing signals that affect cell survival, phenotype and gene expression.

Section snippets

Introduction: the cardiac extracellular matrix

The cardiac extracellular matrix is critical to maintaining the structural integrity of the heart. Disruption of the matrix network results in alterations of the ventricular geometry and is associated with both systolic and diastolic dysfunction [1], [2], [3]. Perhaps the most dramatic changes in the composition of the cardiac extracellular matrix occur in the setting of acute myocardial infarction. Cardiomyocyte death triggers an intense inflammatory reaction leading to infiltration of the

How does the extracellular matrix modulate the inflammatory and reparative response?

Because the heart has negligible regenerative capacity, myocardial infarction ultimately results in replacement of dead cardiomyocytes with a collagen-based scar. From a descriptive viewpoint, the cellular and molecular events involved in the reparative response can be divided in three overlapping phases (Fig. 1). Cardiomyocyte death rapidly triggers cytokine, chemokine and adhesion molecule expression initiating the inflammatory phase and leading to recruitment of leukocytes in the infarct. As

The cardiac matrix during the inflammatory phase of infarct healing

Cardiomyocyte death triggers rapid activation of the complement system, generates free radicals and activates Toll-Like Receptor (TLR)-mediated pathways. These overlapping pathways activate Nuclear Factor (NF)-κB in resident myocardial cells inducing expression of cytokines, chemokines and adhesion molecules [9]. Adhesive interactions between leukocytes and activated endothelial cells ultimately result in infiltration of the infarcted myocardium with neutrophils and mononuclear cells. During

The cardiac extracellular matrix during the proliferative phase of infarct healing

The transition from the inflammatory to the proliferative phase is associated with activation of pathways that inhibit pro-inflammatory signals while promoting fibrous tissue deposition and angiogenesis. The infarct environment becomes highly cellular; activated myofibroblasts proliferate and secrete extracellular matrix proteins while endothelial cells form microvessels that provide oxygen and nutrients to the healing wound. The matrix alterations during the proliferative phase of healing

The matrix during the maturation phase

Collagen content in the healing infarct progressively increases with time [57]. As the scar matures increased expression of cross-linking enzymes, such as lysyl-oxidase induces matrix cross-linking in the infarcted myocardium [58]. Formation of a mature scar comprised of dense cross-linked collagen enhances tensile strength of the infarct while increasing passive stiffness and contributing to diastolic dysfunction [59]. During the maturation phase, most myofibroblasts and vascular cells are

Conclusions

The role of the extracellular matrix in the infarcted myocardium extends beyond providing mechanical support. Matrix-related pathways are critically involved in the reparative process and provide essential environmental cues that determine cell survival, phenotype and gene expression. Several key questions need to be answered in order to understand the role of the dynamic alterations in the extracellular matrix of the infarct in the pathogenesis of cardiac remodeling (Table 1). Unfortunately,

Acknowledgments

Supported by NIH R01 HL-76246 and R01 HL-85440.

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