Metalloproteinases and Hypertrophic Cardiomyopathy: A Systematic Review (original) (raw)
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Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy
American Heart Journal, 2008
Background Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. An increase in extracellular matrix produces interstitial fibrosis, by raised amounts of collagen type I/III. Regions of myocardial late gadolinium enhancement by cardiac magnetic resonance (CMR) represented increased myocardial collagen. Regarding the role of matrix metalloproteinases (MMPs) in myocardial remodeling and subsequent fibrosis, the aim of our study was to explore the relation between MMP system and myocardial late gadolinium enhancement by CMR (as expression of image-documented fibrosis) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (as a marker of cardiac overload) in HCM.
Matrix metalloproteinases, tissue inhibitors of metalloproteinases, and heart failure outcomes
International Journal of Cardiology, 2011
Heart failure (HF) prevalence continues to increase and is associated with a high mortality, morbidity, and cost burden for the society . The most common cause of HF in the United States is coronary artery disease . Left ventricular (LV) dysfunction, irrespective of the cause of heart failure (HF), leads to perturbed wall stress resulting in remodeling and HF progression. Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that are involved in the protein degradation in the extracellular matrix and play an important role in remodeling . Multiple classes of MMPs have been identified in human myocardium . Certain MMPs, specifically MMP-2, MMP-3, and MMP-9 have been shown to have high expression in the left ventricle . Tissue inhibitors of metalloproteinases (TIMPS) are low-molecular-weight molecules that bind to MMPs forming MMP-TIMP complexes that exhibit an inhibitory control on MMPs. Several studies have delineated the relationship between MMPs and TIMPs, and that the changes in the MMP/TIMP ratio correlate with left ventricular hypertrophy and dilation . Loss of inhibitory control of TIMP on MMP correlates with progression of left ventricular remodeling via increased MMP activity, extracellular matrix proteolysis, and myocardial remodeling changes . There have been conflicting reports on MMPs and TIMPs levels association with HF outcomes . These studies have generally not assessed the multiple members of the MMP and TIMP family simultaneously and have assessed varying HF outcomes. In this study, we sought to assess the association between multiple MMPs and TIMPs with clinical outcomes, health status, and exercise capacity among HF patients.
Circulation. Heart failure, 2012
Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a risk factor for ventricular arrhythmia. Fibrosis can be reflected in circulating matrix remodeling protein concentrations. We explored differences in circulating markers of extracellular matrix turnover between young HCM patients with versus without history of serious arrhythmia. Using multiplexed and single ELISA, matrix metalloproteinases (MMPs) 1, 2, 3, and 9; tissue inhibitor of metalloproteinases (TIMPs) 1, 2, and 4; and collagen I carboxyterminal peptide (CICP) were measured in plasma from 45 young HCM patients (80% male patients; median age, 17 years [interquartile range, 15-20]). Participants were grouped into serious ventricular arrhythmia history (VA) versus no ventricular arrhythmia history (NoVA). Differences in MMPs between groups were examined nonparametrically. Relationships between MMPs and ventricular arrhythmia were assessed with linear regression, adjusted for interventricular septal thic...
Molecular and Cellular Biochemistry, 2005
Background: Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM. Methods: Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed. Results: Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285 ± 10 μM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue. Conclusions: Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy. (Mol Cell Biochem 264: 183–191, 2004)
The role of matrix metalloproteinases in heart disease
Cardiovascular Research, 1996
lar matrix also contains hetero-polysaccharides (glycosaminoglycans), glycoproteins (heparan sulphate and chondroitin sulphate proteoglycans), microfibrillar proteins (fibrillin and fibulin) and elastin.
Collagen I and III, MMP-1 and TIMP-1 immunoexpression in dilated cardiomyopathy
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2017
The extracellular matrix (ECM) remodeling represents the pathological substrate of dilated cardiomyopathy (DCM). In this study, we statistically analyzed the immunoexpression of collagen I and III, matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor-1 (TIMP-1) in the myocardial tissue in 18 cases of DCM compared to a control group. We observed a significant increase in the immunoexpression of collagen I and III in patients with DCM and a significant reduction in the immunoexpression of MMP-1 compared with the control group. Also, the collagen I and TIMP-1 expression indicated a positive linear correlation and respectively a negative linear relationship with collagen III and MMP-1. The analyzed markers in this study can be used to quantify the degree of collagen sclerosis from the ECM of DCM.
Matrix metalloproteinases and their function in myocardium
Biomedical papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia, 2005
A significant number of myocardial diseases are accompanied by increased synthesis and degradation of the extracellular matrix (ECM) as well as by changed maturation and incorporation of ECM components. Important groups of enzymes responsible for both normal and pathological processes in ECM remodeling are matrix metaloproteinases (MMPs). These enzymes share a relatively conserved structure with a number of identifiable modules linked to their specific functions. The most important function of MMPs is the ability to cleave various ECM components; including such rigid molecules as fibrillar collagen molecules. The amount and activity of MMPs in cardiac tissue are regulated by a range of activating and inhibiting processes. Although MMPs play multifarious roles in many myocardial diseases, here we have focused on their function in ischemic cardiac tissue, dilated cardiomyopathy and hypertrophied cardiac tissue. The inhibition of MMPs by means of synthetic inhibitors seems to be a prom...
Matrix Metalloproteinases Repress Hypertrophic Growth in Cardiac Myocytes
Cardiovascular Drugs and Therapy
Purpose Matrix metalloproteinases (MMPs) are identified as modulators of the extracellular matrix in heart failure progression. However, evidence for intracellular effects of MMPs is emerging. Pro- and anti-hypertrophic cardiac effects are described. This may be due to the various sources of different MMPs in the heart tissue. Therefore, the aim of the present study was to determine the role of MMPs in hypertrophic growth of isolated rat ventricular cardiac myocytes. Methods Cardiomyocytes were isolated form ventricular tissues of the rat hearts by collagenase perfusion. RT-qPCR, western blots, and zymography were used for expression and MMP activity analysis. Cross-sectional area and the rate of protein synthesis were determined as parameters for hypertrophic growth. Results MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14 mRNAs were detected in cardiomyocytes, and protein expression of MMP-2, MMP-9, and MMP-14 was identified. Hypertrophic stimulation of cardiomyocytes did not enhance, but in...
Cardiovascular Research, 2000
Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-b in the failing human heart before and after left ventricular assist device support, as well as the possibility of 1 preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.
Role of extracellular matrix metalloproteinases in cardiac remodelling
Heart Failure Reviews, 1996
The latent collagenolytic system is an intrinsic part of normal myocardium. Controlled activation of this system becomes necessary in ventricular chamber remodeling following inflammation and injury, such as dilated cardiomyopathy and myocardial infarction. Evidence exists to indicate activation of collagenolytic enzymes in patients with congestive heart failure and dilated, dysfunctional ventricles due to cardiomyopathy and ischemic heart disease.