Tissue Inhibitor of Metalloproteinase (TIMP) Interactions
Published by Anonymous on 2007/9/26 (3181 reads)
1: Heart Fail Rev. 2004 Jan;9(1):21-31.
Myocardial remodeling in viral heart disease: possible interactions between inflammatory mediators and MMP-TIMP system.
Pauschinger M, Chandrasekharan K, Schultheiss HP.
Department of Cardiology, University Hospital Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. pauschinger@ukbf.fu-berlin.de
Matrix metalloproteinases (MMP), a family of proteases, are involved in the degradation of extracellular matrix proteins and hence in the determination of interstitial architecture. In the heart, MMPs have been found to play a significant role in the development of myocardial remodeling and congestive heart failure. Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of proteins which are known to regulate the expression and activity of MMPs. TIMPs are endogenous physiological inhibitors of MMPs and their concomitant downregulation in heart failure suggests the existence of a critical balance between MMPs and TIMPs in the normal maintenance of myocardial interstitial homeostasis. In addition, cytokines regulate expression of both MMPs and TIMPs besides eliciting a direct effect on myocardial cell function. Therefore, myocardial inflammation may also contribute to the development of cardiac remodeling along with other stimuli like mechanical stress and humoral factors. Viral myocarditis, a predisposing factor for dilated cardiomyopathy, is a condition in which extent of intramyocardial inflammation is thought to determine the progression of disease. Inflammatory events in the heart following viral infection are speculated to be responsible for the transition of myocarditis to dilated cardiomyopathy. In viral myocarditis and other inflammatory heart diseases, the inflammatory cells and their battery of cytokines may also alter the myocardial MMP-TIMP system and eventually lead to dilation of the heart and ventricular dysfunction. The objective of this review is to present an overall picture of the inflammatory phase in viral myocarditis and discuss the possible interactions between inflammation and myocardial MMP profiles which may lead to the evolution of dilated cardiomyopathy.
Publication Types:
Review
PMID: 14739765 [PubMed - indexed for MEDLINE]
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2: Ann N Y Acad Sci. 1999 Jun 30;878:73-91.
Insights into MMP-TIMP interactions.
Bode W, Fernandez-Catalan C, Grams F, Gomis-Rüth FX, Nagase H, Tschesche H, Maskos K.
Max-Planck-Institut für Biochemie, Martinsried, Germany. bode@biochem.mpg.de
The proteolytic activity of the matrix metalloproteinases (MMPs) involved in extracellular matrix degradation must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance can result in serious diseases such as arthritis and tumor growth and metastasis. Knowledge of the tertiary structures of the proteins involved in such processes is crucial for understanding their functional properties and to interfere with associated dysfunctions. Within the last few years, several three-dimensional structures have been determined showing the domain organization, the polypeptide fold, and the main specificity determinants of the MMPs. Complexes of the catalytic MMP domains with various synthetic inhibitors enabled the structure-based design and improvement of high-affinity ligands, which might be elaborated into drugs. Very recently, structural information also became available for some TIMP structures and MMP-TIMP complexes, and these new data elucidated important structural features that govern the enzyme-inhibitor interaction.
Publication Types:
Review
PMID: 10415721 [PubMed - indexed for MEDLINE]
Myocardial remodeling in viral heart disease: possible interactions between inflammatory mediators and MMP-TIMP system.
Pauschinger M, Chandrasekharan K, Schultheiss HP.
Department of Cardiology, University Hospital Benjamin Franklin, Free University Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. pauschinger@ukbf.fu-berlin.de
Matrix metalloproteinases (MMP), a family of proteases, are involved in the degradation of extracellular matrix proteins and hence in the determination of interstitial architecture. In the heart, MMPs have been found to play a significant role in the development of myocardial remodeling and congestive heart failure. Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of proteins which are known to regulate the expression and activity of MMPs. TIMPs are endogenous physiological inhibitors of MMPs and their concomitant downregulation in heart failure suggests the existence of a critical balance between MMPs and TIMPs in the normal maintenance of myocardial interstitial homeostasis. In addition, cytokines regulate expression of both MMPs and TIMPs besides eliciting a direct effect on myocardial cell function. Therefore, myocardial inflammation may also contribute to the development of cardiac remodeling along with other stimuli like mechanical stress and humoral factors. Viral myocarditis, a predisposing factor for dilated cardiomyopathy, is a condition in which extent of intramyocardial inflammation is thought to determine the progression of disease. Inflammatory events in the heart following viral infection are speculated to be responsible for the transition of myocarditis to dilated cardiomyopathy. In viral myocarditis and other inflammatory heart diseases, the inflammatory cells and their battery of cytokines may also alter the myocardial MMP-TIMP system and eventually lead to dilation of the heart and ventricular dysfunction. The objective of this review is to present an overall picture of the inflammatory phase in viral myocarditis and discuss the possible interactions between inflammation and myocardial MMP profiles which may lead to the evolution of dilated cardiomyopathy.
Publication Types:
Review
PMID: 14739765 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Ann N Y Acad Sci. 1999 Jun 30;878:73-91.
Insights into MMP-TIMP interactions.
Bode W, Fernandez-Catalan C, Grams F, Gomis-Rüth FX, Nagase H, Tschesche H, Maskos K.
Max-Planck-Institut für Biochemie, Martinsried, Germany. bode@biochem.mpg.de
The proteolytic activity of the matrix metalloproteinases (MMPs) involved in extracellular matrix degradation must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance can result in serious diseases such as arthritis and tumor growth and metastasis. Knowledge of the tertiary structures of the proteins involved in such processes is crucial for understanding their functional properties and to interfere with associated dysfunctions. Within the last few years, several three-dimensional structures have been determined showing the domain organization, the polypeptide fold, and the main specificity determinants of the MMPs. Complexes of the catalytic MMP domains with various synthetic inhibitors enabled the structure-based design and improvement of high-affinity ligands, which might be elaborated into drugs. Very recently, structural information also became available for some TIMP structures and MMP-TIMP complexes, and these new data elucidated important structural features that govern the enzyme-inhibitor interaction.
Publication Types:
Review
PMID: 10415721 [PubMed - indexed for MEDLINE]
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