Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives

2004 ◽  
Vol 42 (2) ◽  
Author(s):  
Jean-Louis Beaudeux ◽  
Philippe Giral ◽  
Eric Bruckert ◽  
Marie-José Foglietti ◽  
M. John Chapman
Keyword(s):  
Matrix Metalloproteinases ◽  
Atherosclerotic Lesion ◽  
Left Ventricular ◽  
Vascular Pathology ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Remodelling ◽  
Plaque Instability ◽  
Plaque Disruption ◽  
Extracellular Matrix Remodelling ◽  
Metalloproteinase Activity

AbstractMatrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.

Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo

2000 ◽  
Vol 279 (2) ◽  
pp. H601-H609 ◽  
Author(s):  
Li Lu ◽  
Zeenat Gunja-Smith ◽  
J. Frederick Woessner ◽  
Philip C. Ursell ◽  
Teo Nissen ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Active Form ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Contractile Dysfunction ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Fourfold Increase

Severe ischemic injury or infarction of myocardium may cause activation of matrix metalloproteinases (MMPs) and damage the interstitial matrix. However, it is unknown whether MMP activation and matrix damage occur after moderate ischemia and reperfusion that result in myocardial stunning without infarction, and if so whether such changes contribute to postischemic myocardial expansion and contractile dysfunction. To address these questions, open-chest anesthetized pigs underwent 90 min of regional ischemia (subendocardial blood flow 0.4 ± 0.1 ml · g−1 · min−1) and 90 min of reperfusion. After ischemia plus reperfusion, histological and ultrastructural examination revealed no myocardial infarction or inflammatory cell infiltration. Myocardial MMP-9 content increased threefold with a fourfold increase in the active form ( P < 0.001). Myocardial collagenase content doubled ( P < 0.01) but remained in latent form. MMP-2 and tissue inhibitors of metalloproteinases were unaffected. Despite increases in MMPs, collagen ultrastructure (assessed by cell maceration scanning electron microscopy) was unaltered. Intracoronary administration of the MMP inhibitor GM-2487 did not prevent or attenuate myocardial expansion (assessed by regional diastolic dimensions at near-zero left ventricular pressure) or contractile dysfunction. We conclude that although moderate ischemia and reperfusion alter myocardial MMP content and activity, these effects do not result in damage to interstitial collagen, nor do they contribute to myocardial expansion or contractile dysfunction.

scholarly journals Relationships between Circulating Matrix Metalloproteinases, Tissue Inhibitor TIMP-2, and Renal Function in Patients with Myocarditis

2021 ◽  
pp. 1-9
Author(s):  
Małgorzata Kobusiak-Prokopowicz ◽  
Konrad Kaaz ◽  
Dominik Marciniak ◽  
Bożena Karolko ◽  
Andrzej Mysiak
Keyword(s):  
Renal Function ◽  
Matrix Metalloproteinases ◽  
Ejection Fraction ◽  
Kidney Diseases ◽  
Serum Levels ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Left Ventricular Ejection ◽  
Longitudinal Deformation ◽  
Ventricular Ejection Fraction

<b><i>Introduction:</i></b> Under physiological conditions, the myocardial extracellular matrix (ECM) is maintained by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). However, changes in the balance between MMPs and TIMPs can lead to pathological remodeling of the ECM, which contributes to cardiovascular and kidney diseases. The aim of our study was to assess levels of MMPs and TIMP-2 in patients with myocarditis and their relationship to renal function. <b><i>Materials and Methods:</i></b> Forty five patients with myocarditis who underwent CMR were included, comprising 11 with concurrent chronic kidney disease (CKD). Blood samples were obtained to assess serum levels of MMP-2, MMP-3, MMP-9, and TIMP-2. <b><i>Results:</i></b> Serum MMP-2, MMP-3, and TIMP-2 levels negatively correlated with the ejection fraction in patients with myocarditis, while MMP-3 levels correlated with longitudinal deformation (<i>p</i> &#x3c; 0.05). Serum MMP-2, MMP-3, and TIMP-2 levels also negatively correlated with renal function, as assessed by the estimated glomerular filtration rate (eGFR) (<i>p</i> &#x3c; 0.05). Patients with myocarditis and concurrent CKD had higher levels of MMP-2 and TIMP-2 than those without kidney damage. <b><i>Conclusions:</i></b> (1) We demonstrated that MMP-2, MMP-3, and TIMP-2 concentrations were related to left-ventricular ejection fraction, and MMP-3 levels correlated with longitudinal deformation, indicating MMPs play an important role in the post-inflammatory remodeling of the myocardium. (2) A negative correlation between the eGFR and MMP-2, MMP-3, and TIMP-2 and a positive correlation between creatinine and MMP-3 levels indicate the role of MMPs and TIMP-2 in renal dysfunction.

scholarly journals Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction

2010 ◽  
Vol 299 (4) ◽  
pp. H1012-H1023 ◽  
Author(s):  
Vijay Kandalam ◽  
Ratnadeep Basu ◽  
Thomas Abraham ◽  
Xiuhua Wang ◽  
Ahmed Awad ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Matrix Metalloproteinases ◽  
Diastolic Dysfunction ◽  
Second Harmonic ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Ecm Remodeling ◽  
Infarct Expansion

Extracellular matrix (ECM) remodeling is a critical aspect of cardiac remodeling following myocardial infarction. Tissue inhibitors of metalloproteinases (TIMPs) are physiological inhibitors of matrix metalloproteinases (MMPs) that degrade the ECM proteins. TIMP3 is highly expressed in the heart, and is markedly downregulated in patients with ischemic cardiomyopathy. We therefore examined the time- and region-dependent role of TIMP3 in the cardiac response to myocardial infarction (MI). TIMP3−/− and wild-type (WT) mice were subjected to MI by ligation of the left anterior descending artery. TIMP3−/−-MI mice exhibited a significantly compromised rate of survival compared with WT-MI mice, primarily due to increased left ventricular (LV) rupture, greater infarct expansion, exacerbated LV dilation, and greater systolic and diastolic dysfunction. Second harmonic generation imaging of unfixed and unstained hearts revealed greater collagen disarray and reduced density in the TIMP3−/− infarct myocardium compared with the WT group. Gelatinolytic and collagenolytic activities increased in TIMP3−/− compared with WT hearts at 1 day post-MI but not at 3 days or 1 wk post-MI. Neutrophil infiltration and inflammatory MMPs were significantly increased in the infarct and peri-infarct regions of TIMP3−/−-MI hearts. Treatment of TIMP3−/− mice with a broad-spectrum MMP inhibitor (PD-166793) for 2 days before and 2 days after MI markedly improved post-MI infarct expansion, LV rupture incident, LV dilation, and systolic dysfunction in these mice up to 1 wk post-MI. Our data demonstrate that the initial rise in proteolytic activities early post-MI is a triggering factor for subsequent LV adverse remodeling, LV rupture, and dilated cardiomyopathy. Hence, timing of treatments to improve cardiac response to MI may be critical in producing favorable outcome.

scholarly journals Effects of genistein on the periovulatory expression of messenger ribonucleic acid for matrix metalloproteinases and tissue inhibitors of metalloproteinases in the rat ovary

Reproduction ◽  
2001 ◽  
pp. 259-265 ◽  
Author(s):  
CM Komar ◽  
M Matousek ◽  
K Mitsube ◽  
M Mikuni ◽  
M Brannstrom ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Tyrosine Kinases ◽  
Rna Isolation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Remodelling ◽  
Rnase Protection ◽  
Tissue Inhibitors ◽  
Messenger Ribonucleic Acid ◽  
Gelatinases A And B

The matrix metalloproteinases (MMPs) play critical roles in the ovulatory process. Their expression and activity, together with those of the endogenous tissue inhibitors of metalloproteinases (TIMPs), are stimulated by LH. The LH surge initiates a cascade of events resulting in ovulation and formation of the corpus luteum via activation of protein kinases A and C, as well as tyrosine kinases. In vitro perfused rat ovaries were untreated, or treated with LH (0.2 microg ml(-1)) plus 0.2 mmol 3-isobutyl-1-methylxanthine l(-1) with 0, 10 or 100 micromol genistein l(-1) (an inhibitor of tyrosine kinases) to assess whether tyrosine kinases are mediators of the LH-stimulated increase in ovarian expression of the MMPs and TIMPs. After 10 h of perfusion, ovaries were collected and frozen until RNA isolation. Northern and RNase protection analyses were used to measure mRNA encoding collagenase 3, gelatinases A and B, and TIMPs-1, -2 and -3. Treatment with LH plus 3-isobutyl-1-methylxanthine resulted in a two- and fivefold increase in mRNA encoding collagenase 3 and TIMP-1, respectively (P < 0.05). Treatment with 100 micromol genistein l(-1) blocked the LH-stimulated increase in collagenase 3 (0.012 +/- 0.002 versus 0.028 +/- 0.005 relative units for 100 micromol genistein l(-1) versus LH; P < 0.05), whereas neither dose of genistein affected LH-induced TIMP-1 expression. LH alone or with genistein did not alter the expression of mRNA encoding TIMP-2 and TIMP-3, or mRNA encoding gelatinases A and B. These data indicate that tyrosine kinases play a role in the LH-induced tissue remodelling required for ovulation by mediating the LH-stimulated expression of collagenase 3.

Matrix metalloproteinases in stroke

2017 ◽  
pp. 110-117
Author(s):  
А.А. Пальцын
Keyword(s):  
Matrix Metalloproteinases ◽  
Enzyme System ◽  
Enzyme Complex ◽  
Pathogenic Factors ◽  
Pathogenic Action ◽  
Activity Of Enzymes ◽  
Living Tissues ◽  
Current Reconstruction ◽  
Metalloproteinase Activity

Матриксные металлопротеиназы - ферментный комплекс, необходимый для сохранения гомеостаза. Он участник нормальной, постоянно текущей реконструкции всех живых тканей. Действие патогенных факторов нарушает слаженную работу этого комплекса. Часто нарушение выражается излишней активностью ферментов, усиливающей патогенное действие. Однако и заживление, форсированное новообразование тканевых элементов, может происходить только при повышенной, в сравнении с нормой, активности металлопротеиназ. Такая ситуация требует от медицины умения разумно вмешиваться в работу ферментной системы. В статье представлены некоторые результаты этих вмешательств. Matrix metalloproteinases - enzyme complex necessary for maintenance of the homeostasis. He is a participant of normal, constantly current reconstruction of all living tissues. Action of pathogenic factors breaks harmonious work of this complex. Often violation is expressed by the excessive activity of enzymes amplifying pathogenic action. However and healing, which is accelerated new growth of tissue elements, can happen only at raised, compared with norm, metalloproteinase activity. Such situation demands from medicine of ability participate reasonably in work of enzyme system. The article presents some of the results of these actions.

Role of Matrix Metalloproteinases in Degenerative Kidney Disorders

2018 ◽  
Vol 25 (15) ◽  
pp. 1805-1816 ◽  
Author(s):  
Shifa Narula ◽  
Chanderdeep Tandon ◽  
Simran Tandon
Keyword(s):  
Matrix Metalloproteinases ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β1 ◽  
Bioactive Molecules ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Ecm Remodeling ◽  
Surface Receptors ◽  
Calcium Dependent ◽  
Ecm Degradation

Matrix metalloproteinases (MMPs) are members of calcium dependent-zinc containing endopeptidases that play a pivotal role in extracellular matrix (ECM) remodeling. MMPs are also known to cleave non-matrix proteins, including cell surface receptors, TNF-α, angiotensin-II, growth factors, (especially transforming growth factor-β1, ΤGF- β1) plasminogen, endothelin and other bioactive molecules. The tissue inhibitors of metalloproteinases (TIMPs) inhibit the activity of MMPs and decrease ECM degradation. Various patho-physiological conditions have been linked with the imbalance of ECM synthesis and degradation. Numerous studies have reported the significance of MMPs and TIMPs in the progression of kidney pathologies, including glomerulonephritis, diabetic nephropathy, renal cancer, and nephrolithiasis. Although dysregulated activity of MMPs could directly or indirectly lead to pathological morbidities, their contribution in disease progression is still understated. Specifically, MMP activity in the kidneys and it's relation to kidney diseases has been the subject of a limited number of investigations. Therefore, the aim of the present review is to provide an updated insight of the involvement of MMPs and TIMPs in the pathogenesis of inflammatory and degenerative kidney disorders.

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