Cardiac Extracellular Matrix and its Role in the Development of Heart Failure

Summary

The major protein components of cardiac extracellular matrix include collagen, fibronectin, and elastin. Collagen is by far the predominant component of the cardiac extracellular matrix, and it has been shown that heart muscle contains five isoforms of this protein, including types I, III, IV, V, and VI. Of these, collagen types I and III are most abundant and represent more than 90% of all collagen proteins in the myocardium. Recent investigation of regulation of these proteins indicates that the synthesis and degradation of cardiac collagens are mediated by several key peptide and cytokine factors. Cardiac collagen concentration (fibrosis) is dependent upon the balance struck between the synthetic and degradative pathways, which are assessed by transcriptional and translational studies of specific collagen genes and cardiac collagenase activity, respectively. Recent studies indicate that the extracellular matrix plays an important role in the remodeling of the myocardium in various types of experimental heart failure. Clinical studies also demonstrate that extracellular matrix proteins are altered in patients suffering from end-stage heart failure of different etiologies. It is suggested that increased deposition of extracellular matrix may impair normal heart function. In this regard, inappropriate deposition of collagen may reduce right and left ventricular chamber compliance, and may thereby affect both positive and negative cardiac inotropism. As these changes may accelerate the development of heart failure, pharmacologic management of synthetic/degradative pathways of extracellular matrix components should be a priority for effective treatment of heart failure.

In any given organ, the volume displaced by constitutive cells may account for a fraction of the total volume of the tissue. Thus a substantial amount of organ volume is occupied by a complex network of macromolecules that is defined as the extracellular matrix and physically connects the constitutive cells. In most organs the extracellular matrix is composed of a variety of polysaccharides and proteins that are secreted by fibroblast cells [1]. The major components of the extracellular matrix include 1) the structural proteins, such as collagens and elastin; 2) cell adhesive or antiadhesive molecules, including fibronectin, vitronectin, laminin, and tenascin; and 3) proteoglycans, which are a complex array of proteins linked to glycosaminoglycan side chains. In the heart, cardiac myocytes occupy ∼75% of the total tissue space but represent only one third of the total cell number.

The nonmyocyte cells reside in the cardiac interstitium and account for about two thirds of the total cell population. These cell types include cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. Cardiac fibro-blasts exist in large numbers in the heart and form the largest group among cardiac nonmyocyte cells [2,3]. Recent data indicate that the cardiac extracellular matrix plays a critical role in the function of both normal and failing myocardium [4]. It is becoming clear that extracellular matrix proteins are not merely involved in serving only as the cellular scaffolding for the myocardium per se but may significantly contribute to cardiac function. As some recent biochemical and molecular studies have led to a burgeoning knowledge of the general characteristics of the cardiac stromal tissue and as much recent work in various experimental models has addressed the role of extracellular matrix in the diseased heart, we have undertaken a review of these topics. This review summarizes the structure and function of cardiac extracellular matrix, factors in the regulation of the synthesis and degradation of the extracellular matrix, and the role of the extracellular matrix in heart failure.