doi: 10.1161/01.RES.0000142315.88477.42
© 2004 American Heart Association, Inc.
Editorials |
Cell–Matrix Signaling and Thrombospondin
Another Link to Myocardial Matrix Remodeling
From the Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina and RHJ Department of Veterans Affairs Medical Center, Charleston, SC.
Correspondence to Francis G. Spinale, Cardiothoracic Surgery, Rm 625, Strom Thurmond Research Bldg, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425. E-mail wilburnm{at}musc.edu
See related article, pages 515–522
Key Words: hypertrophy • extracellular matrix • thrombospondin • matrix metalloproteinase
Thrombospondins (TSP) are a family of secreted glycoproteins that participate in cell-to-matrix communication through a number of different pathways.1–8 Although TSP were first identified as a protein released by platelets after exposure to thrombin (hence the origin of the name of this family of proteins), it is now recognized that TSP are released by a number of cell types. TSP are secreted into the extracellular matrix (ECM) and interact with a number of important bioactive molecules, such as transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF).1,2,4,9,10 In general terms, TSP appear to modulate cell/matrix interactions through the coalescence of membrane proteins and signaling molecules at specific contact points on the cell surface.1,2,5,6 These sites of TSP/protein interactions at the cell surface, which then induce intracellular signaling events, include the integrins as well as integrin-associated proteins such as CD36 and CD47. Although 5 members of the TSP family exist, the best-studied are TSP-1 and TSP-2. The biological properties of TSP-1 and TSP-2 appear to be similar in general terms, but there are structural differences in TSP-1 and TSP-2 that may impart some unique functions with respect to cell-matrix signaling.11–14 In this issue, Schroen et al report a potential role of myocardial TSP-2 in the adaptive and maladaptive remodeling that occurs in left ventricular hypertrophy (LVH).15 To place the findings of this study in context with emerging studies regarding myocardial ECM remodeling and the progression to LV failure, a brief review of the biology of TSP with respect to matrix signaling and remodeling is presented here.
One of the more established functions of TSP-1, and likely that of TSP-2, is to proteolytically process latent TGF-ß to an active form.1,2,9 Through fusion protein studies and the development of a TSP-1 null mouse, it has been established that a specific domain on the TSP molecule (domain type I) proteolytically processes latent TGF-ß into the mature peptide.16,17 Active TGF-ß induces profound effects on the ECM through the induction of fibrillar collagen expression and synthesis.18,19 An important proteolytic pathway for ECM degradation is through the synthesis, release, and activation of the matrix metalloproteinases (MMP).20,21 The MMP are a large family of zinc-dependent enzymes that degrade a large portfolio of ECM components, activate other latent MMP, as well as other bioactive molecules. One point of post-translational regulation of MMP activity is through covalent binding to the tissue inhibitors of MMP (TIMP). Thus the stoichiometric balance between MMP and TIMP is an important determinant of myocardial ECM structure and composition. Past in vitro studies have demonstrated that TGF-ß causes the activation of several transcription factors that reduce the expression of certain MMP and increases the expression of TIMP.22 Whereas TSP-mediated activation of TGF-ß directly affects ECM structure and function, it also appears that a TSP/TGF-ß complex is formed, which in turn binds to the integrin-associated proteins CD36 and CD47.1,2 It is likely that these TSP/TGF-ß membrane complexes mediate a number of intracellular events through the p38 mitogen-activated protein kinase (P38MAPK) pathway, as well as through the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway.1,2,22,23 The activation of these signaling pathways by these TSP/TGF-ß complexes will also change the expression profile of ECM proteins, MMP, and TIMP. Finally, in vitro studies have demonstrated that a specific TSP domain binds to MMP directly and can modulate MMP activation.11,13 By a number of pathways, both direct and indirect, TSP can induce myocardial ECM accumulation through both increased synthesis and diminished degradation.
TSP can modify important cell-matrix interactions through several other processes, which include modifying endothelial, vascular smooth muscle cell, and fibroblast growth and viability. A great deal of research interest has been on the effects of TSP on angiogenesis.1–4,7,8,10,23,24 It appears that both TSP-1 and TSP-2 can inhibit angiogenesis in certain in vivo models.1,2,7,8 These effects appear to be mediated through extracellular interactions with a number of growth factors, including PDGF.1,2,23 TSP can modify endothelial and fibroblast adhesion to ECM components.1,2,11,13 Exposure of vascular smooth muscle cells to TSP resulted in activation of focal adhesion kinase, which in turn would modify cell-matrix binding.25 TSP can mediate apoptosis in endothelial cells by a p38MAPK signaling pathway.23 The functional role that TSP plays in a number of critical cell-matrix events has been investigated, to some degree, in TSP-1 and TSP-2 transgenic mice.12,13,26 The consequences of TSP mutations and gene deletions are incompletely understood, but in the TSP-1 null mouse, abnormalities in lung function have been described.26 Specifically, in TSP-1 null mice, a consolidated pneumonia occurs associated with heightened inflammation and endothelial cell hyperplasia. These defects were likely attributable, in part, to diminished TSP-mediated TGF-ß processing because TGF-ß null mice exhibit a very similar pulmonary pathology.27 These transgenic experiments further demonstrated that one likely pathway by which TSP modifies the ECM is through a TGF-ß-dependent mechanism. Although TSP-1 and TSP-2 are structurally similar, there are differences that have been observed in the TSP-2 null mouse, suggesting some unique functions of TSP-2.1,2,11–13 In wound healing models, TSP-2 null mice demonstrated alterations in wound closure, and that the major source of TSP-2 at the site of injury appeared to be the fibroblast.28 In TSP-2 null mice, abnormalities in ECM structure and composition have been reported.11,14 In these transgenic mice, collagen fibril disarray and abnormally large fibrils were observed in skin and tendon samples. Furthermore, fibroblasts isolated from the TSP-2 null mice demonstrated abnormal ECM adhesion. Finally, the relative levels of the gelatinase class of MMP (MMP-2) were increased significantly in the TSP-2 null mice.11,13 Through in vitro assays, it was demonstrated that TSP-2 may have an important role in the extracellular clearance of MMP-2 by fibroblasts.14,24 Thus the spatio-temporal induction of TSP-2 within the interstitium will directly affect ECM remodeling, which in turn will influence tissue structure and function.
Therefore, the critical role of TSP in the ECM remodeling processes is becoming recognized, and a simplified summary of some of the important pathways by which TSP can modify the matrix is shown in Figure 1. Although TSP is expressed in relatively robust levels in myocardium, there have been few studies that have examined the role of TSP in cardiac disease states. A past report has demonstrated that TSP-1 was increased in myocardial biopsy specimen taken from patients with postcardiac transplant vasculopathy.29 However, there have not been any definitive studies that provide a mechanistic link between TSP induction and the progression of LV remodeling and failure. The study by Schroen et al provide some unique insight into the potential role of TSP-2 in LVH and the progression to failure.15 This study used 3 approaches to examine TSP-2 with respect to LV remodeling and failure. In the first set of experiments, a renin transgenic rat model that results in the increased release of angiotensin II (ang II), the development of LVH, and the progression to LV failure was used. Through gene array studies, it was demonstrated that TSP-2 was increased in the transgenic LVH rats. These investigators went on to demonstrate through biopsy measurements that TSP-2 was selectively increased in those rats that progressed to LV failure, but was not increased in those rats that maintained an LVH phenotype and did not progress to failure. In a second set of experiments, Shroen et al demonstrated that an ang II infusion caused cardiac rupture in a large number of TSP-2 null mice; in surviving TSP-2 null mice, rapid cardiac decompensation occurred. Finally, these investigators demonstrated higher myocardial levels of TSP-2 in patients with LVH secondary to aortic stenosis, which were particularly elevated in patients with reduced ejection fractions. The authors concluded that TSP-2 is essential for adaptation to an LV pressure load, but persistently elevated levels of TSP-2 may be maladaptive and contribute to progressive LV failure.
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The results found by Schroen et al regarding the putative role of TSP-2 in LV remodeling and failure are provocative in several ways. First, increased levels of TSP-2 were identified in rodents and humans with LVH. Because TSP induces increased collagen synthesis and inhibits degradation, these observations suggest that TSP-2 may be contributory for the increased myocardial ECM, which invariably occurs in LVH. Second, it was demonstrated that an infusion of ang II caused myocardial rupture in TSP-2 null mice. In those TSP-2 null mice that survived the infusion, myocardial collagen content was reduced and relative levels of the MMP gelatinase class, MMP-2 and MMP-9, were increased. These observations are consistent with abnormalities in the ECM reported previously in the TSP-2 null mouse.11,14 Further, these observations support the role of TSP-2 in the inhibition of MMP activity through direct binding and by facilitating active MMP clearance. Third, there was an association between heightened levels of TSP-2 in rats with LVH and failure, as well as in humans with LVH and reduced ejection performance. Although these studies are associative, they do emphasize the important temporal duality of function with respect to ECM proteins and interstitial bioactive molecules in the LV remodeling process. Specifically, these results demonstrated the importance of early signals and proteolytic events to induce myocardial ECM remodeling after the induction of a pressure overload. As evidenced in the study by Shoen et al,15 the loss of TSP-2-mediated signaling caused ECM remodeling and myocardial rupture with an acute increase in LV load. However, continued ECM remodeling in LVH, potentially mediated in part by TSP, will adversely affect myocardial structure and function and, in turn, contribute to the progression to LV failure. A similar theme of duality of function is emerging with respect to myocardial MMP and ECM remodeling after myocardial infarction.20,21 Specifically, early MMP activation is likely to be essential for the normal wound healing response after myocardial infarction, but prolonged MMP activation may cause adverse ECM remodeling and LV failure. Because TSP-2 can influence MMP expression and activation, the inter-relationship of these ECM molecules after myocardial infarction and in other relevant forms of cardiac disease states would be warranted. Another important avenue of future inquiry is to determine whether and to what degree myocardial TGF-ß processing and signaling were affected by TSP-2 deletion. In a mouse model of atrial natriuretic peptide deletion and LVH, TSP was significantly increased.30 It is interesting to note that in the present study by Shoen et al, brain natriuretic peptide levels appeared to be independent of TSP expression, suggesting multiple regulatory pathways for TSP.15 Nevertheless, this study provides further evidence that the myocardial ECM is a dynamic environment that contains a wide portfolio of bioactive signaling molecules and growth factors, proteases, and structural proteins. Further understanding of how ECM proteins that influence cell-matrix interactions (ie, matricellular modulators1,2), such as TSP, will likely yield important insight into the critical pathways that regulate myocardial matrix structure and function.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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