Emerging role of matrix metalloproteinases in the pathophysiology of cardiac diseases.

Abstract

As other organs, the heart is composed of highly differentiated, very specialized parenchymal cells (cardiomyocytes) surrounded by stroma consisting of extracellular matrix (ECM), tissue fluid and undifferentiated, pluripotent mesenchymal cells. The maintenance of matrix integrity involves the synthesis and degradation of its major components, including collagens, glycoproteins, glycosaminoglycans and proteoglycans. The ECM-degrading proteinases can be subdivided into three main classes: serine proteinases, metalloproteinases and cysteine proteinases. Matrix metalloproteinases (MMPs) make up a family of more than 20 zinc-containing endoproteinases that can be subdivided into four groups based on their substrate specificity and primary structure [1]. The first group, the collagenases, include MMP-1 (interstitial collagenase), MMP-8 (neutrophil collagenase) and MMP-13 (collagenase 3), which can all cleave fibrillar collagens (types I, II and III). Group 2, the gelatinases (MMP-2 and MMP-9), is well known for its ability to degrade gelatins and type IV collagen in basement membranes. Group 3 constitutes the stromelysins (MMP-3, MMP-10 and MMP-11), so named because they are active against a broad spectrum of ECM components, including proteoglycans, laminins, fibronectin, vitronectin and some types of collagens. Group 4 contains the membrane-type MMPs (MT-MMPs), which degrade several ECM components and are also able to activate other MMPs. The expression of MMPs is regulated at the transcriptional level by a variety of inflammatory cytokines, hormones and growth factors [1]. In addition, a cell-surface protein that induces MMP expression, termed extracellular matrix metalloproteinase inducer (EMMPRIN) has been identified recently in a number of tissue types, including human myocardium [2]. The MMPs, first synthesized as inactive zymogen precursors, must be activated by proteolytic cleavage. Fully activated MMPs can be inhibited by interaction with naturally occurring, specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs; 1–4) [3]. Thus, the actual activity of MMPs depends on the rate of synthesis, activation, and the balance between active enzyme and inhibitors. Form the pioneer work by Montfort and Perez-Tamayo [4] it is well known that MMPs are present in the normal myocardium. Myocardial MMPs are produced by fibroblastlike cells and inflammatory cells, as well cardiomyocytes [5,6], and they are predominantly present in their latent form [7]. Emerging evidence is giving rapid momentum to the concept that dysregulation of myocardial MMPs and secondary alterations in ECM degradation modulate major features of myocardial pathology and, thus, mediate crucial steps in the development of heart failure [8]. This recognition provides new insight into the pathogenesis of cardiac diseases and further provides new potential targets for intervening [9]. Myocardial fibrosis may illustrate well the above concept. Myocardial fibrosis is the end result of altered ECM turnover, where synthesis of matrix proteins, namely fibrillar type I and III collagens, exceeds their degradation [10]. It is becoming clear that fibrosis is not a unique pathological process but is due to excess in the same biological events involved in normal tissue repair. A central event in tissue repair is the release of cytokines in response to injury. Several lines of evidence point to transforming growth factor-β (TGF-β) as a key cytokine that initiates and terminates tissue repair and whose sustained production underlies the development of tissue fibrosis [11]. Although all three isoforms of TGF-β (TGF-β1, -β2 and -β3) are present in the heart, the level of the type 1 isoform seems to be particularly related to the development of myocardial fibrosis. Transgenic mice overexpressing TGFβ1 exhibit fibrosis of the heart and other organs [12]. In contrast, age-associated myocardial fibrosis is diminished in heterozygous TGF-β1-deficient mice [13]. The fibrogenic potential of TGF-β1 is uniquely powerful because of its simultaneous ability to stimulate matrix synthesis and to inhibit matrix degradation. In fact, it has been shown that Division of Cardiovascular Pathophysiology, School of Medicine, and Department of Cardiology and Cardiovascular Surgery, University Clinic. University of Navarra, Pamplona, Spain (J. Diez).