Left ventricular remodeling: one small step for the extracellular matrix will translate to a giant leap for the myocardium.

Myocardial infarction (MI) is initiated by an acute disruption of blood supply. Prolonged ischemia in the region downstream of the occlusion culminates with tissue necrosis. Inflammation follows the induction of necrosis and orchestrates the wound healing response. Key components of wound healing are the recruitment and engagement of leukocytes and the reorganization of the extracellular matrix (ECM). Due to the poor regenerative capacity of the heart, cardiomyocyte loss is compensated by the generation of a collagen-based ECM scar. The early post-MI scar is mainly composed of collagen III, but as the collagen scar maturates, the ratio of collagen types changes towards a predominance of collagen I. Long-term outcomes post-MI depend on the quality of scar formed, in terms of quantity, quality, and extent of cross-linking. The irreversible changes in the biomechanics and geometry of the left ventricle (LV) are collectively known as LV remodeling, and adverse LV remodeling stimulates the progression to congestive heart failure. The most promising treatments for the MI patient involve detection pre-MI to avert ischemia, early diagnosis to limit myocyte loss during ischemia, or targeting mechanisms that occur during resolution of the inflammatory and fibrotic responses to prevent the progression to heart failure (Figure 1). As such, understanding how the ECM influences remodeling will identify novel targets for clinical intervention. Open in a separate window Figure 1 Reorganization of the ECM during post-MI remodeling The adult mammalian heart is characterized by a myocardium that is highly organized with an overlapping layered structure, and the ECM scaffold surrounds and support the cells of the myocardium. ECM is mainly composed of fibrillar collagen that provides structural strength through its three-dimensional structure that interdigitates between cardiac muscle fibers. As such, the ECM plays a pivotal role in the transmission of contractile forces. Collagen I accounts for approximately 70–85% of total cardiac collagen in the LV and provides tensile strength, whereas collagen III accounts for about 10% of total cardiac collagen. The thin collagen III fibers maintain the elasticity of the ECM network.1 In addition to collagen and other glycoproteins, glycosaminoglycans, basement membrane components, and proteoglycans are components of the ECM.2 In addition to providing an environment for cells, ECM also serves as a reservoir for growth factors and proteases. Under normal conditions, ECM homeostasis is maintained by signaling interactions between cardiac cells and matrix proteins through cell surface receptors, e.g., integrins. Prolonged ischemia that turns into irreversible ischemia ultimately leads to cell death, and this event requires ECM network reorganization. Key players in the degradation of ECM are the matrix metalloproteinases (MMPs). Neutrophils are a rich source of MMPs, and neutrophil infiltration occurs as early as 15 minutes after the initiation of reperfusion.3 MMPs cleave collagens and other ECM proteins at site specific locations to generate ECM fragments.4 Early post-MI, this degradation of ECM is accompanied by the continuous generation of a fibrin-based provisional matrix that provides structural support for the infarct region. Necrotic cell debris and matrix fragments activate membrane-bound toll-like receptors, the complement system, high-mobility group box 1, and the receptor for advanced glycation end-products, all of which play important roles in the early steps of the wound healing response, by stimulating the generation of reactive oxygen species and initiating the nuclear factor kB pathway to produce inflammatory cytokines.5,6 Cytokines attract inflammatory cells into the infarcted region, where these cells are activated to initiate scavenging and repair processes. Macrophages infiltrate beginning at day 3 post-MI, serving to engulf necrotic myocytes and apoptotic neutrophils, as well as promote anti-inflammatory processes. Activated macrophages also release growth factors to stimulate collagen synthesis and fibroblast activation, which stimulates formation of the ECM scar.7 Over time, the provisional fibrin-based matrix is degraded by proteolytic enzymes and replaced by a secondary fibroblast-derived matrix containing several ECM proteins, including fibronectin and hyaluronan. At this point, a number of matricellular proteins are released by both fibroblasts and macrophages to orchestrate the signaling pathways responsible for infarct repair. Matricellular proteins, unlike fibrillar ECM components, are not involved in structural roles but rather modulate cell function by interacting with cell-surface receptors, proteases, hormones, and other bioeffector molecules, as well as with structural matrix proteins such as collagens.3 Among the most studied matricellular proteins are thrombospondin (TSP)-1, -2 and -4, secreted protein acidic and rich in cysteine, tenascin-C and -X, osteopontin, periostin, and members of the CCN family (including CCN1 and CCN2/connective tissue growth factor).3 The expression of matricellular proteins in the normal adult myocardium is low and generally is only observed during development or as a response to injury. In the infarct environment, matricellular protein expression rapidly increases. Matricellular proteins stimulate cell migration, proliferation, and adhesion, but also serve crucial roles in mediating the inflammatory response. For example, TSP-1, an important transforming growth factor beta activator with potent angiostatic and anti-inflammatory properties, is significantly increased in the border area between the infarct and remote areas and serves to limit infarct expansion.8 In the infarct environment, cardiac fibroblast cells are important sources of ECM, MMPs, and growth factors that stimulate angiogenesis.9 While the source of the cardiac myofibroblast is controversial, resident and infiltrating cells can undergo phenotypic change to differentiate into myofibroblasts.10,11 Myofibroblasts in particular produce robust amounts of ECM that provides structural support to the infarcted region. Fibroblasts also initiate the contraction of the provisionary matrix deposited in the affected region. Alterations in the composition of ECM over time mediate multiple components of the inflammatory and fibrotic responses.