Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy

Roldán, Vanessa; Marı́n, Francisco; Gimeno, Juan R.; Ruíz-Espejo, Francisco; González, J. M. Rodríguez; Feliu, Eloísa; García-Honrubia, Antonio; Saura, Daniel; Morena, Gonzalo de la; Valdés, Mariano; Vicente, Vicente

doi:10.1016/j.ahj.2008.01.035

Cited by 84 publications

(73 citation statements)

References 31 publications

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“…32 It is also relevant to mention that many other actions independent of matrix degradation have been attributed to MMPs, especially MMP-2, and these actions may be very relevant to cardiac remodelling. 29,33,34 Although we do not have a mechanistic explanation for the associations being reported here, it is clear that complex interactions of factors regulate MMPs activities in the heart. The present study has some limitations.…”

Section: Discussionmentioning

confidence: 66%

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

et al. 2011

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Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C À1306 T (rs243865) and C À735 T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C À1306 T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P ¼ 0.0365 and P ¼ 0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P ¼ 0.0278 and P ¼ 0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P ¼ 0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P ¼ 0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio ¼ 3.5121, 95% confidence interval ¼ 1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling.

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Section: Discussionmentioning

confidence: 66%

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

et al. 2011

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“…41 Other Circulating Biomarkers Whereas parallel changes in myocardial collagen content and serum PINP have been reported in HF patients presenting reverse LV geometric remodeling after prolonged LV assist device support, 42 no significant correlations were found between the 2 parameters. On the other hand, although plasma MMP-9 levels have been found to be associated with late gadolinium enhancement by cardiac magnetic resonance (a potential index of myocardial collagen content) in patients with hypertrophic cardiomyopathy, 43 no data are available in the literature on the association of circulating gelatinases with alterations of the myocardial collagen network in cardiac patients. Finally, there is no available information on serum PIIICP in cardiac diseases.…”

Section: Plasma Timp-1mentioning

confidence: 95%

Circulating Biomarkers of Collagen Metabolism in Cardiac Diseases

2010

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A lterations of the structure and composition of cardiomyocyte and noncardiomyocyte compartments of the myocardium appear to play a central role in the pathogenesis of heart failure (HF) associated with a number of cardiac diseases. Among these alterations, changes in the quantity and quality of the extracellular matrix, including the collagen network, have been characterized that induce remodeling of the myocardium and ultimately deteriorate left ventricular (LV) function and facilitate the development of HF. Studies on circulating biomarkers of collagen metabolism have attracted the attention of the medical community, and some circulating biomarkers have been proposed as potential useful tools to improve diagnosis, prognosis, and therapy in cardiac diseases that develop HF. 1 However, the available data are far from conclusive and from affording incremental value to the knowledge provided by more classic diagnostic tools. This is due mainly to 3 limitations. First, collagen is the most abundant protein in the body, and its turnover is so dynamic that not all circulating molecules proposed as biomarkers actually reflect changes in collagen metabolism, namely at the cardiac level. Second, a thorough understanding of the association of a given biomarker with the pathological features of the collagen network in the cardiac disease under study has not been considered essential, thus weakening its pathophysiological meaning. Third, several methodological issues may introduce a number of confounding factors into the measurements of circulating biomarkers of collagen metabolism, thus bringing into question the validity of the available results. Therefore, this article is not aimed at providing a systematic review of all the published information on circulating biomarkers of collagen metabolism in cardiac diseases but at analyzing the biochemical, pathophysiological, and methodological aspects to be taken into account to overcome the above limitations and to improve the clinical applicability of such molecules. Circulating Biomarkers of Collagen Metabolism Collagen MetabolismThe extracellular matrix contains a fibrillar collagen network, a basement membrane, proteoglycans and glycosaminoglycans, and bioactive signaling molecules. The collagen network is a metabolically active structure in the sense that the balance between the synthesis and degradation of collagen determines its turnover, which is estimated to be from 80 to 120 days. 2 The turnover is regulated by fibroblasts and by fibroblasts differentiated to myofibroblasts (Figure 1). 3 These cells respond to mechanical stretch, autocrine and paracrine factors generated locally (eg, vasoactive peptides such as angiotensin II and growth factors such as transforming growth factor-␤ or connective tissue growth factor), and hormones derived from the circulation (eg, aldosterone). In addition, a number of proinflammatory cytokines (eg, tumor necrosis factor-␣, interleukin-1 and -6) secreted by monocytes and macrophages also influence the function of fibroblasts and my...

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“…12 Our long-term data are also in agreement with previous research showing that pharmacological blockade (with KB-R7785) of ADAM-12 (which we found to be downstream of TACE) does not protect mice from agonist-induced hypertension. 7 Previous studies have found that TACE, ADAM-12, and MMP-2 are all upregulated in human hypertrophic cardiomyopathy 16,21 and that ADAM-12 may mediate agonist-induced cardiac hypertrophy. 7 Recently, a novel role for ADAM-12 was reported in facilitating activation of transforming growth factor-␤ signaling through Smads, which is the main pathway mediating the development of agonist-induced fibrosis.…”

Section: Wang Et Al Regulation Of Cardiac Hypertrophy By Tace 579mentioning

confidence: 99%

Tumor Necrosis Factor-α–Converting Enzyme Is a Key Regulator of Agonist-Induced Cardiac Hypertrophy and Fibrosis

et al. 2009

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Abstract-Cardiac remodeling is associated with hypertrophy and fibrosis processes, which may depend on the activity of matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinases" (ADAMs). We investigated whether ADAM-17 (tumor necrosis factor-␣-converting enzyme [TACE]) plays a role in agonist-induced cardiac remodeling and the relationships established among TACE, MMP-2, and ADAM-12. We targeted TACE in rodent models of spontaneous and agonist-induced hypertension using RNA interference combined with quantitative RT-PCR, activity determinations, and functional studies. Treatment of spontaneously hypertensive rats with previously validated TACE small-interfering RNA for 28 days resulted in systemic knockdown of TACE expression. TACE knockdown effectively stopped the development of cardiac hypertrophy. Mice receiving angiotensin II (1.4 mg/kg per day for 12 days) exhibited cardiac hypertrophy, as well as fibrosis, which was associated with elevated myocardial expression of molecular markers of hypertrophy (␣-skeletal actin, ␤-myosin heavy chain, and brain natriuretic peptide) and fibrosis (collagen types I and III and fibronectin), as well as MMP-2 and ADAM-12. Treatment with TACE small-interfering RNA (but not with PBS or luciferase small-interfering RNA) inhibited TACE expression, thus preventing angiotensin II-induced cardiac hypertrophy and fibrosis. Moreover, knockdown of TACE inhibited angiotensin II-induced overexpression of markers of myocardial hypertrophy and fibrosis, as well as ADAM-12 and MMP-2. These findings provide the first in vivo evidence that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TACE, which acts through novel pathways involving transcriptional regulation of ADAM-12 and MMP-2. Targeting TACE has potential therapeutic importance for modulating agonist-induced cardiac remodeling. Key Words: cardiac hypertrophy Ⅲ hypertension Ⅲ metalloproteinase Ⅲ ADAM-17/TACE Ⅲ Gq protein-coupled receptor agonist Ⅲ RNA interference C ardiac remodeling is a major hallmark of hypertensive disorders and is associated with the development of cardiac hypertrophy (ie, an increase in cell size of individual cardiomyocytes), which causes thickening of the myocardium. Although initially compensatory, sustained hypertrophic growth is pathological, in part, because of its association with the development of fibrosis (ie, increased synthesis and deposition of extracellular matrix proteins), which disrupts the normal structure and contractile properties of the myocardium. 1 Pathological cardiac remodeling is, thus, detrimental for cardiac function and may cause cardiac dysfunction, myocardial stiffness, and increased risk of heart failure, sudden death, and stroke. 2-5 However, it remains unclear how and why such apparently distinct processes as cardiac hypertrophy and fibrosis develop with hypertension and whether pressure overload in hypertension is causal.Our laboratory is investigating the general hypothesis that cardiac remodeling may be associated with hypertens...

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Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy

Cited by 84 publications

References 31 publications

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

Circulating Biomarkers of Collagen Metabolism in Cardiac Diseases

Tumor Necrosis Factor-α–Converting Enzyme Is a Key Regulator of Agonist-Induced Cardiac Hypertrophy and Fibrosis

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