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 fibrinbased 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 collagenbased 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.

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

“…In models of ischemia, in which there has been myocardial injury or infarction, inflammation has been shown to have a key function in healing and likely participates in the development of fibrosis but its contribution to date has been poorly defined. [30][31][32] The complex interactions between ischemia and the development of fibrosis were not explored in this study.…”

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

“…Thus, it is postulated that after MI, activation of calpain induces IB degradation and subsequent NF-B activation, resulting in the expression of proinflammatory cytokines such as TNF-␣ and Mcp-1 in cardiomyocytes, which promote the infiltration of inflammatory cells, contributing to myocardial remodeling (21). In addition, the proinflammatory cytokines released from cardiomyocytes not only act as an autocrine signaling to induce cardiomyocyte apoptosis and hypertrophy, but also as a paracrine signaling to promote fibrosis through fibroblasts after MI (42). As such, cardiac-specific deletion of Capn4, via prevention of IB degradation and NF-B activation, inhibits inflamma- tory responses and blocks both autocrine and paracrine signalings induced by local proinflammatory cytokines from cardiomyocytes, leading to a reduction in myocardial remodeling and an improvement of myocardial function in the MI heart.…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In all three phases of infarct healing, the dynamic changes in the composition of the ECM play a critical role in regulation of the cellular responses that mediate cardiac repair (11). During the inflammatory phase, early degradation of matrix proteins generates bioactive fragments (termed matrikines) that may contribute to activation of inflammatory and reparative cascades (Figure 1).…”

“…Lysis of the plasma-derived provisional matrix is followed by organization of a cell-derived matrix network, comprising cellular fibronectin, hyaluronan, proteoglycans, and a wide range of matricellular macromolecules (39) that transduce growth factor signals to reparative cells (58). The dynamic alterations of the ECM during the proliferative phase provide essential signals for conversion of fibroblasts into myofibroblasts and may activate angiogenic pathways necessary for neovessel formation, thus supplying the metabolically active wound with oxygen and nutrients (11).…”