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

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)-beta 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.

2009 Elsevier Ltd. All rights reserved.

Figures

Figure 1

The phases of infarct healing. Myocardial infarction triggers a reparative response that can be divided in three overlapping phases. During the inflammatory phase, chemokine, cytokine and adhesion molecule expression is upregulated leading to leukocyte recruitment in the infarct. As the acute inflammatory response is suppressed, mesenchymal cells infiltrate the infarct marking the transition to the proliferative phase. Myofibroblasts deposit extracellular matrix while a rich capillary network is formed. During the maturation phase the cellularity of the infarct decreases and the matrix is cross-linked forming a dense collagen-based scar. The images show hematoxylin/eosin-stained sections of reperfused canine infarcts after 1 h coronary occlusion followed by 3 days (inflammatory phase), 7 days (proliferative phase) and 2 months (maturation phase) of reperfusion. The time intervals for each phase are shown for both rodent and large animal models of reperfused infarction. In comparison to large mammals, rodents exhibit an accelerated inflammatory and reparative response following myocardial infarction [50], [19]. Symbols: MCP, Monocyte Chemoattractant Protein-1; IL, Interleukin; MMP, Matrix Metalloproteinase; TNF, Tumor Necrosis Factor; TGF, Transforming Growth Factor; TIMP, Tissue Inhibitor of Metalloproteinases.

Figure 2

Alterations of the extracellular matrix during the inflammatory phase of infarct healing. Protease activation results in degradation of matrix proteins. MMPs also process inflammatory cytokines and chemokines modulating their activity. Generation of collagen and low molecular weight hyaluronan (H) fragments exerts potent pro-inflammatory effects. In addition, fibrinogen (F) and plasma fibronectin (pFN) are extravasated through the hyperpermeable vasculature resulting in formation of a fibrin-based provisional matrix that serves as a scaffold for migration of inflammatory cells (M, mononuclear cell; N, neutrophil).

Figure 3

Alterations of the extracellular matrix during the proliferative phase of infarct healing. As the provisional matrix is lysed and matrix fragments are cleared, fibroblasts (F) and macrophages (Ma) secrete cellular fibronectin (cFN) and hyaluronan (H) forming a “second order” provisional matrix. ED-A fibronectin, TGF-β and mechanical tension due to loss of the shielding effects of the normal matrix, contribute to myofibroblast (MF) differentiation and activation. The matricellular proteins TSP-1, OPN, SPARC and tenascin-C are transiently induced in the infarcted heart and modulate cellular interactions and matrix assembly.

Figure 4

The extracellular matrix during the maturation phase of infarct healing. As the scar matures, lysyl-oxidase upregulation induces collagen cross-linking. Formation of a stable cross-linked extracellular matrix may shield the myofibroblasts (MF) from mechanical tension promoting quiescence. Ultimately, most infarct myofibroblasts undergo apoptosis. Prolonged presence of myofibroblasts in the infarcted myocardium may promote adverse remodeling.