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The extracellular matrix: Summation
Journal of Cardiac Failure Vol. 8 No. 6 Suppl. 2002
The Extracellular Matrix: Summation FRANCIS G. SPINALE, MD, PhD Charleston, South Carolina
The development and progression of left ventricular (LV) dysfunction and, ultimately, the clinical manifestation of congestive heart failure (CHF) is due to the summation of a number of systemic, cellular, and molecular abnormalities. The specific constellation of abnormalities that contribute to the progression of CHF is disease dependent, but it likely includes neurohormonal system activation, changes in LV loading conditions, defects in myocardial perfusion and metabolism, and alterations in excitation-contraction coupling. One common structural feature in the progression of the CHF process is LV myocardial remodeling. Myocardial remodeling can be defined as molecular, cellular, and interstitial changes within the myocardium that result in changes in LV size and function. One of the predominant geometric features of myocardial remodeling that accompanies the CHF process is LV dilation. The progression of LV remodeling is accompanied by alterations in the structure and function of the extracellular matrix (ECM), which in turn likely facilitates the myocardial remodeling process in CHF. Accordingly, a focused session on the myocardial ECM was held at the July 2001 Satellite Meeting of the XVII World Congress of the International Society for Heart Research: Remodeling and Progression of Heart Failure. One goal of this session was to evaluate specific aspects of the myocardial ECM with respect to the LV remodeling process, to define important interfaces between the ECM and the cardiac myocyte, and to provide some avenues for future research. The purpose of this session was not to provide a comprehensive and exhaustive review of past studies. Rather, the purpose was to present a fresh perspective on a particular body of knowledge regarding the myocardial ECM and to identify areas for future basic and clinical
investigation regarding the myocardial ECM and the remodeling process. One of the first studies to describe the anatomic basis of the myocardial ECM was by Caufield and Borg.1 Since that time, it has become well recognized that the ECM is not a static entity but rather a dynamic microenvironment that not only contains structural support proteins but also serves as an important interface with respect to cell-cell signaling. The first monograph, by Goldsmith and Borg, emphasizes the dynamic and diverse nature of the myocardial ECM. An important point made by this introductory presentation is that both biologic and physical stimuli, which are operative through the ECM, directly affect myocyte biology. The development of LV dilation has been shown to be associated with discontinuity and disruptions of the supporting fibrillar collagen network, with decreases in the degree of collagen strut cross-linking, and with disruptions in myocyte adhesion capacity to the basement membrane. The landmark work by Weber et al2 regarding the pressure-overloaded myocardium provides important insight into the significant changes that can occur within the myocardial ECM after the heart undergoes a prolonged pressure overload. The next article in this series, by Janicki and Brower, involves fibrillar collagens being placed into context with material properties of the myocardium. Moreover, the importance of posttranslational processing with respect to collagen cross-linking is emphasized. The integrins, a family of transmembrane proteins, are responsible for myocyte adhesion and interfacing with the ECM. Although they were initially thought to be static anchors for cellular adhesion to the ECM, it is now recognized that the integrins form a critical role in the transduction of extracellular signals, contribute to the maintenance of cytoskeletal architecture, and constitute the initiation point for a cascade of intracellular signaling molecules such as small G-proteins and kinase.3 In the 3rd part of this series, Ross and Borg3 succinctly defines the multiple functions of integrins with respect to influencing myocyte biology and the overall myocardial remodeling process. Historically, the myocardial ECM has been examined through histological/morphometric studies or biochemical assays of frozen myocardial specimens. However, these studies fail to take into account that temporal changes occur within
From Cardiac Surgery, Medical University of South Carolina, Charleston, South Carolina. Reprint requests: Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Bldg, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, South Carolina, 29425. Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0030$35.00/0 doi: 10.1054/jcaf.2002.129257
S349
S350 Journal of Cardiac Failure Vol.8 No. 6 Suppl. 2002 the extracellular space in much more rapid and dynamic fashion. For example, the integration of changes in myocardial ECM structure and function to the elaboration and release of signaling molecules will require additional analytical approaches. In another contribution to this series, future approaches that might be employed to further our understanding of matrix-cellular interactions within the myocardium are proposed by Lee and Lammerding. These investigators define how the use of transgenic murine models provides insight into the role of the matrix metalloproteinases (MMPs) with respect to myocardial ECM remodeling. They also look to the future regarding the role of proteonomics to further our understanding of this complex proteolytic system. In the next article, a current review of the MMPs is provided, and an attempt is made to place this proteolytic system into context of human heart failure and myocardial remodeling. Moreover, future directions regarding modulating MMP expression and activity during the development and progression of heart failure process is briefly presented. The final article in this series, by Creemers et al, 4 examines the myocardial ECM remodeling process with respect to myocardial infarction (MI). Furthermore, these investigators describe potentially exciting new results regarding the use of genetic models as well as pharmacological approaches that are directly targeted at modulating ECM remodeling after MI.
One conclusion that can be drawn from this particular series is that the myocardial ECM is not a passive entity but rather a complex and dynamic microenvironment representing an important structural and signaling system within the myocardium. Future research focused on the molecular and cellular mechanisms that regulate ECM structure and function will likely contribute to improved understanding of the LV remodeling process in CHF as well as yield novel therapeutic targets.
References 1. Caulfield JB, Borg TK: The collagen network of the heart. Lab Invest 1979;4:364–372 2. Weber KT, Janicki JS, Shroff S: Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 1988;2:757–765 3. Ross RS, Borg TK: Integrins and the myocardium. Circ Res 2001;88(11):1112–1119 4. Creemers EEJM, Cleutjens JPM, Smits JFM, Daemen MJAP: Matrix metalloproteinase inhibition after myocardial infarction. A new approach to prevent heart failure? Circ Res 2001;89;201–210
The Extracellular Matrix: Summation FRANCIS G. SPINALE, MD, PhD Charleston, South Carolina
The development and progression of left ventricular (LV) dysfunction and, ultimately, the clinical manifestation of congestive heart failure (CHF) is due to the summation of a number of systemic, cellular, and molecular abnormalities. The specific constellation of abnormalities that contribute to the progression of CHF is disease dependent, but it likely includes neurohormonal system activation, changes in LV loading conditions, defects in myocardial perfusion and metabolism, and alterations in excitation-contraction coupling. One common structural feature in the progression of the CHF process is LV myocardial remodeling. Myocardial remodeling can be defined as molecular, cellular, and interstitial changes within the myocardium that result in changes in LV size and function. One of the predominant geometric features of myocardial remodeling that accompanies the CHF process is LV dilation. The progression of LV remodeling is accompanied by alterations in the structure and function of the extracellular matrix (ECM), which in turn likely facilitates the myocardial remodeling process in CHF. Accordingly, a focused session on the myocardial ECM was held at the July 2001 Satellite Meeting of the XVII World Congress of the International Society for Heart Research: Remodeling and Progression of Heart Failure. One goal of this session was to evaluate specific aspects of the myocardial ECM with respect to the LV remodeling process, to define important interfaces between the ECM and the cardiac myocyte, and to provide some avenues for future research. The purpose of this session was not to provide a comprehensive and exhaustive review of past studies. Rather, the purpose was to present a fresh perspective on a particular body of knowledge regarding the myocardial ECM and to identify areas for future basic and clinical
investigation regarding the myocardial ECM and the remodeling process. One of the first studies to describe the anatomic basis of the myocardial ECM was by Caufield and Borg.1 Since that time, it has become well recognized that the ECM is not a static entity but rather a dynamic microenvironment that not only contains structural support proteins but also serves as an important interface with respect to cell-cell signaling. The first monograph, by Goldsmith and Borg, emphasizes the dynamic and diverse nature of the myocardial ECM. An important point made by this introductory presentation is that both biologic and physical stimuli, which are operative through the ECM, directly affect myocyte biology. The development of LV dilation has been shown to be associated with discontinuity and disruptions of the supporting fibrillar collagen network, with decreases in the degree of collagen strut cross-linking, and with disruptions in myocyte adhesion capacity to the basement membrane. The landmark work by Weber et al2 regarding the pressure-overloaded myocardium provides important insight into the significant changes that can occur within the myocardial ECM after the heart undergoes a prolonged pressure overload. The next article in this series, by Janicki and Brower, involves fibrillar collagens being placed into context with material properties of the myocardium. Moreover, the importance of posttranslational processing with respect to collagen cross-linking is emphasized. The integrins, a family of transmembrane proteins, are responsible for myocyte adhesion and interfacing with the ECM. Although they were initially thought to be static anchors for cellular adhesion to the ECM, it is now recognized that the integrins form a critical role in the transduction of extracellular signals, contribute to the maintenance of cytoskeletal architecture, and constitute the initiation point for a cascade of intracellular signaling molecules such as small G-proteins and kinase.3 In the 3rd part of this series, Ross and Borg3 succinctly defines the multiple functions of integrins with respect to influencing myocyte biology and the overall myocardial remodeling process. Historically, the myocardial ECM has been examined through histological/morphometric studies or biochemical assays of frozen myocardial specimens. However, these studies fail to take into account that temporal changes occur within
From Cardiac Surgery, Medical University of South Carolina, Charleston, South Carolina. Reprint requests: Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Bldg, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, South Carolina, 29425. Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0030$35.00/0 doi: 10.1054/jcaf.2002.129257
S349
S350 Journal of Cardiac Failure Vol.8 No. 6 Suppl. 2002 the extracellular space in much more rapid and dynamic fashion. For example, the integration of changes in myocardial ECM structure and function to the elaboration and release of signaling molecules will require additional analytical approaches. In another contribution to this series, future approaches that might be employed to further our understanding of matrix-cellular interactions within the myocardium are proposed by Lee and Lammerding. These investigators define how the use of transgenic murine models provides insight into the role of the matrix metalloproteinases (MMPs) with respect to myocardial ECM remodeling. They also look to the future regarding the role of proteonomics to further our understanding of this complex proteolytic system. In the next article, a current review of the MMPs is provided, and an attempt is made to place this proteolytic system into context of human heart failure and myocardial remodeling. Moreover, future directions regarding modulating MMP expression and activity during the development and progression of heart failure process is briefly presented. The final article in this series, by Creemers et al, 4 examines the myocardial ECM remodeling process with respect to myocardial infarction (MI). Furthermore, these investigators describe potentially exciting new results regarding the use of genetic models as well as pharmacological approaches that are directly targeted at modulating ECM remodeling after MI.
One conclusion that can be drawn from this particular series is that the myocardial ECM is not a passive entity but rather a complex and dynamic microenvironment representing an important structural and signaling system within the myocardium. Future research focused on the molecular and cellular mechanisms that regulate ECM structure and function will likely contribute to improved understanding of the LV remodeling process in CHF as well as yield novel therapeutic targets.
References 1. Caulfield JB, Borg TK: The collagen network of the heart. Lab Invest 1979;4:364–372 2. Weber KT, Janicki JS, Shroff S: Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 1988;2:757–765 3. Ross RS, Borg TK: Integrins and the myocardium. Circ Res 2001;88(11):1112–1119 4. Creemers EEJM, Cleutjens JPM, Smits JFM, Daemen MJAP: Matrix metalloproteinase inhibition after myocardial infarction. A new approach to prevent heart failure? Circ Res 2001;89;201–210