Role Of Matrix Metalloproteinases Research Articles

Different roles of matrix metalloproteinase2 in osteolysis of skeletal dysplasia and bone metastasis (Review).

Matrix metalloproteinase 2 (MMP2) is a well-characterized protein that is indispensable for extracellular matrix remodeling and other pathological processes, such as tumor progression and skeletal dysplasia. Excessive activation of MMP2 promotes osteolytic metastasis and bone destruction in late-stage cancers, while its loss-of-function mutations result in the decreased bone mineralization and generalized osteolysis occurring progressively in skeletal developmental disorders, particularly in multicentric osteolysis, nodulosis and arthropathy (MONA). Either upregulation or downregulation of MMP2 activity can result in the same osteolytic effects. Thus, different functions of MMP2 have been recently identified that could explain this observation. While MMP2 can degrade bone matrix, facilitate osteoclastogenesis and amplify various signaling pathways that enhance osteolysis in bone metastasis, its role in maintaining the number of bone cells, supporting osteocytic canalicular network formation and suppressing leptin-mediated inhibition of bone formation has been implicated in osteolytic disorders caused by MMP2 deficiency. Furthermore, the proangiogenic activity of MMP2 is one of the potential mechanisms that are associated with both pathological situations. In the present article, the latest research on MMP2 in bone homeostasis is reviewed and the mechanisms underlying the role of this protein in skeletal metastasis and developmental osteolysis are discussed.

Cysteine cathepsins are altered by flow within an engineered in vitro microvascular niche.

Throughout the process of vascular growth and remodeling, the extracellular matrix (ECM) concurrently undergoes significant changes due to proteolytic activity—regulated by both endothelial and surrounding stromal cells. The role of matrix metalloproteinases has been well-studied in the context of vascular remodeling, but other proteases, such as cysteine cathepsins, could also facilitate ECM remodeling. To investigate cathepsin-mediated proteolysis in vascular ECM remodeling, and to understand the role of shear flow in this process, in vitro microvessels were cultured in previously designed microfluidic chips and assessed by immunostaining, zymography, and western blotting. Primary human vessels (HUVECs and fibroblasts) were conditioned by continuous fluid flow and/or small molecule inhibitors to probe cathepsin expression and activity. Luminal flow (in contrast to static culture) decreases the activity of cathepsins in microvessel systems, despite a total protein increase, due to a concurrent increase in the endogenous inhibitor cystatin C. Observations also demonstrate that cathepsins mostly co-localize with fibroblasts, and that fibrin (the hydrogel substrate) may stabilize cathepsin activity in the system. Inhibitor studies suggest that control over cathepsin-mediated ECM remodeling could contribute to improved maintenance of in vitro microvascular networks; however, further investigation is required. Understanding the role of cathepsin activity in in vitro microvessels and other engineered tissues will be important for future regenerative medicine applications.

The Role of Matrix Metalloproteinases in Wound Healing

The Role of Matrix Metalloproteinases in Wound Healing

The role of matrix metalloproteinase-2 on age-dependent arterial stiffness

Abstract Introduction Arterial stiffness is a well-characterized sign of vascular aging. It strongly predicts the development of several cardiovascular diseases (CVD), such as hypertension, stroke and heart failure. The age-dependent stiffening of elastic arteries is primarily attributed to the loss of interlaminar elastic fibers and the increase of collagen fibers. This process is regulated by matrix metalloproteinases (MMPs), including MMP-2. A strong correlation between MMP-2 levels and arterial stiffness has been previously described. However, the causative link between age-dependent arterial stiffness and MMP-2 remains unclear. Purpose In this study, we aimed to prospectively investigate the effect of MMP-2 gene silencing on the development of age-dependent carotid stiffness in wild type (WT) mice. Methods Pulse Wave Velocity (PWV), as the gold standard technique to assess arterial stiffness, was assessed in the right common carotid artery (RCCA) of C57BL/6 WT mice of various ages ranging between 3 and 25 months. Plasma and vascular levels of MMP-2 on RCCA were also measured and correlate with PWV. Moreover, aged WT male mice (18–21-month-old) were treated for 4 weeks with either MMP-2 siRNA or Scr siRNA via tail vein injection every 4 days and PWV was assessed at baseline, 2 and 4 weeks. Results Mouse carotid PWV increased and was positively correlated with age in our in vivo longitudinal study. Increases of vascular and circulating MMP-2 levels were also observed in this study. MMP-2 knockdown by siRNA treatment reduced vascular MMP-2 level (Fig. 1), which in turn attenuated age-dependent carotid stiffening (data not shown). siMMP-2 treated animals also showed an increase of elastin to collagen ratio. Furthermore, enhanced phosphorylation of the activatory eNOS Ser1177 was observed in the siMMP-2 group without affecting the level of total eNOS and Akt phosphorylation. Interestingly, co-immunoprecipitation experiments demonstrated that MMP-2 directly interacts with eNOS and this interaction is augmented with age. Conclusion The silencing of MMP-2 attenuates age-dependent carotid stiffness by affecting elastin to collagen ratio and interfering with eNOS activation. Thus, MMP-2 may mediate ECM remodeling and endothelial-dependent vasorelaxation in the development of age-dependent vascular stiffness. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swiss National Science Foundation, Foundation for Cardiovascular Research-Zurich Heart House

The Role of Matrix Metalloproteinase-9 in Atherosclerotic Plaque Instability.

Matrix metalloproteinase-9 (MMP-9) belongs to the MMP family and has been widely investigated. Excessive MMP-9 expression can enhance extracellular matrix degradation and promote plaque instability. Studies have demonstrated that MMP-9 levels are higher in vulnerable plaques than in stable plaques. Additionally, several human studies have demonstrated that MMP-9 may be a predictor of atherosclerotic plaque instability and a risk factor for future adverse cardiovascular and cerebrovascular events. MMP-9 deficiency or blocking MMP-9 expression can inhibit plaque inflammation and prevent atherosclerotic plaque instability. All of these results suggest that MMP-9 may be a useful predictive biomarker for vulnerable atherosclerotic plaques, as well as a therapeutic target for preventing atherosclerotic plaque instability. In this review, we describe the structure, function, and regulation of MMP-9. We also discuss the role of MMP-9 in predicting and preventing atherosclerotic plaque instability.

The role of matrix metalloproteinases in early and late gonarthrosis manifestations

The aim of this research was to study the specifics of the matrix metallopeptidase system in early and late gonarthrosis (GA) manifestations. Material and Methods — 37 patients of the main group (0-I stages of GA), 30 patients of the comparison group (III-IV stages of GA) and 30 healthy individuals of the control group underwent sonography and T2-relaxometry of their knee joints. The 24-h excretion of urinary C-telopeptide fragments of type II collagen (СTX-II) as well as serum concentrations of matrix metalloproteinases-3 and -8 (MMP-3, MMP-8), and tissue inhibitor of metalloproteinases (TIMP-1) were also registered. Results — We detected increases in urinary СTX-II to 3.9 [2.5; 4.5] mg/d, MMP-8 to 364.7 [215; 434] pg/ml and TIMP-1 to 806 [559; 1157] pg/ml in the main group; to 9.7 [6.8; 10.2] mg/d, 579 [463; 663] pg/ml and 1256 [1029; 1330] pg/ml in the comparison group. The presence (p=0.04) of strong positive correlation (R=0.7) between the 24-h urinary СTX-II excretion and the change of MRI-signal characteristics for the areas of hyaline cartilage under the heaviest load on knee joints T2 relaxometry evidence was observed as well as the presence (p=0.001) of strong positive correlation (R=0.7) between MMP-8 and 24-h urinary СTX-II extraction. In early GA stages a strong positive correlation (R=0.6) was observed between MMP-8 and TIMP-1 (p=0.04) as well as 24-h urinary СTX-II excretion and TIMP-1 (R=0.5) at p˂0.001). Conclusion — Type II collagen degradation with MMP-8/TIMP-1 imbalance is one of the relevant mechanisms of the hyaline articular cartilage extracellular matrix disorganization in early and late GA evidences. The rearrangement of correlations between MMP-8 and TIMP-1 indicates the change in interaction mechanisms for GA proteolytic enzyme system components.

Matrix Metalloproteinase-12 Is Required for Granuloma Progression.

BackgroundSarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation.MethodsC57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1).ResultsPulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days.ConclusionsThe striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

Role of Matrix Metalloproteinase-9 in Diagnosis of Dry Eye

Abstract Background: Dry eye is a “multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface”. Symptoms of dry eye, which include visual disturbances and pain/dysesthesias, have been found to negatively impact quality of life. Aim of Study: To assess the presence of ocular surface Matrix Metalloproteinase-9 (MMP-9) in dry eye by Infla-mmaDry® test. Patients and Methods: A prospective cross-sectional study included a total of 40 eyes with dryness. This study was involved patients visiting outpatient clinic in Qalawoon Hospital from December 2018 till May 2019. The tear film was analyzed for MMP-9 by InflammaDry®test, symptoms and signs of dry eye disease were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire, Tear Breakup Time (TBUT), corneal staining, Schirmer and Meibomian gland examination. Results: Mean age of the study population was 39.45 years ±9.06 SD (range 30-60), sixty five percent of study population were females. Mean of Ocular Surface Disease Index was 23.05±5.00 SD (14-33 range), Schirmer test mean was 4.60mm/5 minutes ± 2.11 SD (1-8mm/5min range), Tear Breakup Time mean was 5.40 seconds ±1.61 SD (3-9 range) and corneal staining mean was 2.45±0.68 SD (2-4 range). Seventy five percent of the study population had Meibomian glad dysfunction. There was a highly statistically significant correlation between InflammaDry® results and Meibomian glands dysfunction. There were statistically non-significant correlations between Ocular surface disease index, Schirmer test results, tear breakup time, corneal staining and positive results of InflammaDry®test. Conclusion: There is direct correlation between inflam-mation and dry eye disease. Also, Matrix metalloproteinase testing in dry eye disease is a valuable new diagnostic tool to identify the presence of ocular surface inflammation.

Promising fields in the study of the pathogenesis of necrobiosis lipoidica

The diagnosis of necrobiosis lipoidica is gaining significance owing to the increase in the incidence of diabetes mellitus. Several theories regarding the etiopathogenesis of necrobiosis lipoidica indicate the distinctive role of transport proteins of the Glut family, as well as the role of matrix metalloproteinase in the development of this dermatosis.

The Contribution of MMP-9 Genotypes to Pterygium in Taiwan.

The studies about the roles of matrix metalloproteinases (MMPs) in pterygium diagnosis and/or prognosis are mainly based on their mRNA and protein levels, while the genomic roles of MMPs are seldom examined. The aim of this study was to investigate the contribution of MMP-9 genotypes to pterygium risk. MMP-9 rs3918242 was genotyped in 134 pterygium cases and 268 controls via polymerase chain reaction-restriction fragment length polymorphism. The rs3918242 genotype percentages of CC, CT, and TT were 73.1, 25.4 and 1.5% among cases and 74.6, 23.1 and 2.3% among controls (p trend=0.7928). The odds ratios after adjusting for age and gender for CT and TT genotypes at rs3918242 were 1.08 and 0.92 (95%CI=0.66-1.73 and 0.45-2.89, p=0.6478 and 0.6389), respectively. In addition, allelic frequency analysis showed no significant difference in the distribution of allelic frequencies between the pterygium and control groups. The genotypes at MMP-9 rs3918242 play a minor role in determining personal susceptibility to pterygium.

The Role of Matrix Metalloproteinases in Periodontal Disease.

This review provides a detailed description of matrix metalloproteinases (MMPs), focusing on those that are known to have critical roles in bone and periodontal disease. Periodontal disease is an inflammatory process initiated by anaerobic bacteria, which promote the host immune response in the form of a complex network of molecular pathways involving proinflammatory mediators such as cytokines, growth factors, and MMPs. MMPs are a family of 23 endopeptidases, collectively capable of degrading virtually all extracellular matrix (ECM) components. This study critically discusses the available research concerning the involvement of the MMPs in periodontal disease development and progression and presents possible therapeutic strategies. MMPs participate in morphogenesis, physiological tissue turnover, and pathological tissue destruction. Alterations in the regulation of MMP activity are implicated in the manifestation of oral diseases, and MMPs comprise the most important pathway in tissue destruction associated with periodontal disease. MMPs can be considered a risk factor for periodontal disease, and measurements of MMP levels may be useful markers for early detection of periodontitis and as a tool to assess prognostic follow-ups. Detection and inhibition of MMPs could, therefore, be useful in periodontal disease prevention or be an essential part of periodontal disease therapy, which, considering the huge incidence of the disease, may greatly improve oral health globally.

The role of matrix metalloproteinase-9 in the genesis of chronic bronchi inflammation in children with bronchial asthma

Bronchial asthma as the most common respiratory tract disease is an urgent problem of modern medicine. Matrix metalloproteinases (MMР) play a significant role in the processes of inflammation maintaining and bronchi remodeling in children with bronchial asthma.Objective:To study the role and inheritance of MMR9 in the bronchial asthma pathogenesis in children.Characteristics of children and research methods.The authors carried out the prospective study of 54 children with bronchial asthma and 56 healthy children with the determination of the MMP-9 level in blood serum, as well as the polymorphic variant 8202A>G ofMMP9gene.Results.Children with bronchial asthma had significantly higher content of MMP9 in the blood serum (431.76 [306.15; 612.93] ng/ml), as compared to the control group (276.05 [160.33; 397.02] ng/ml). When studying polymorphism 8202A>G ofMMP9gene in the examined patients it was found that the children with bronchial asthma had the G allele a little more often (57.5%) than A allele (42.5%). Heterozygous carriers of the MMP9 gene polymorphic variant predominate both among the patients with bronchial asthma and in the control group. When comparing the frequency of genotypes and alleles in the group of children with bronchial asthma and control group the authors revealed no statistically significant differences.Conclusion.The disease mechanism significantly depends upon the MMR9 concentration in the serum of patients with bronchial asthma and the peculiarities of this enzyme inheritance.

The Role of Matrix Metalloproteinases (MMP-2 and MMP-9) in Ageing and Longevity: Focus on Sicilian Long-Living Individuals (LLIs).

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers.

The role of matrix metalloproteinases and their inhibitors in physiopathological processes in children with kidney diseases

The review of studies of international and national researchers on the impact of matrix metalloproteinases (matrix metalloproteinases, ММРs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) on physiological and pathological processes in children with kidney diseases. It is shown that MMPs play a significant role in organogenesis, i.e. nephrogenesis. Thus, MMP-2, MMP-9 and TIMPs play a large role in basal membranes remodeling associated with epithelial structures in a developing kidney. Immunohistochemistry assay showed that MMP-2 was localized in structures of immature nephrons undergoing epithelial differentiation, MMP-9 – only in vascular structures included in immature glomeruli. Decreased activity of MMP and /or increased synthesis of TIMPs in nephrocytes contribute to the reduction of intercellular substance components catabolism and serve as a basis for glomerular fibrosis and renal interstitium. MMPs are the major group of proteases which regulate metabolism in extracellular matrix and serve as the most important parameters in tissue remodeling observed in acute and chronic inflammatory processes in kidneys. The literature review gives an opportunity to assess the importance of drug design preventing and delaying the progression of nephrosclerosis.

Role of Matrix Metalloproteinase 9 in Ocular Surface Disorders.

(1) To explore the role and significance of Matrix Metalloproteinase 9 (MMP-9), a proteolytic enzyme, in various ocular surface diseases of inflammatory, infectious, and traumatic etiology (2), to further elucidate the molecular mechanisms responsible for its overexpression in ocular surface disease states, and (3) to discuss possible targets of therapeutic intervention. A literature review was conducted of primary sources from 1995 onward using search results populated from the US National Library of Medicine search database. MMP-9 overexpression has been found in in vitro and in vivo models of dry eye disease (DED), corneal ulceration, microbial keratitis, corneal neovascularization, ultraviolet light-induced radiation, and a host of additional surface pathologies. MMP-9 is involved in an intricate signal transduction cascade that includes induction by many proinflammatory molecules including interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a), nuclear factor kappa light chain enhancer of activated B cells (NF-kB), platelet-activating factor, activator protein 1 (AP-1), and transforming growth factor beta (TGF-B). MMP-9 expression is blunted by a diverse array of molecular factors, such as tissue inhibitors of metalloproteinases, cyclosporine A (CyA), PES_103, epigalloccatechin-3-gallate (EGCG), N-acetylcysteine (NaC), ascorbate, tetracyclines, and corticosteroids. Inhibition of MMP-9 frequently led to improvement of ocular surface disease. Novel insights into the mechanistic action of MMP-9 provide potential for new therapeutic modulations of ocular surface diseases mediated by its overexpression.

Beneficial effects of N-acetylcysteine on protease-antiprotease balance in attenuating bleomycin-induced pulmonary fibrosis in rats.

Objective(s):The role of N-acetylcysteine (NAC) as an anti-oxidant in attenuating bleomycin-induced pulmonary fibrosis has been reported. However, its effect on parenchymal remodeling via regulating the protease-antiprotease balance is not fully defined. Therefore, the present study was designed to explore the possible role of matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and transforming growth factor-β1 (TGF-β1) pathway and their modulation by NAC in attenuating bleomycin-induced pulmonary fibrosis in rats.Materials and Methods:Bleomycin sulphate (7 units/kg) was instilled inside the trachea to induce pulmonary fibrosis. The time course of TGF-β1, MMP-9, TIMP-1,3 mRNA and protein expression, TGF-β1 and hydroxyproline levels were evaluated on days 7, 14, and 28. NAC (0.3 mmol/kg and 3 mmol/kg) was administered in bleomycin-instilled animals.Results:NAC treatment significantly attenuated bleomycin-induced histopathological changes by decreasing interstitial inflammation and reducing the deposition of extracellular matrix proteins such as collagen. Moreover, it increased the mRNA and protein expression of MMP-9 and decreased the expression of TIMP-1,3 in alveolar epithelial cells (AECs), interstitial macrophages and inflammatory cells. Indeed, there was decrease in the MMP-9/TIMP ratio in bleomycin-instilled rats, which increased with NAC treatment. Moreover, NAC attenuated bleomycin-induced increased expression of TGF-β1 and total lung collagen levels.Conclusion:NAC attenuates bleomycin-induced pulmonary fibrosis by normalizing the protease-antiprotease balance and favoring the degradation of collegen to reduce fibrosis.

Histological, Immunohistochemical, Morphometric and Molecular Changes in the Wall of Human Varicose Veins

Abstract Background: Varicose veins (VVs) are a major chronic venous disease, yet the underlying mechanisms are unclear. This disorder is characterized by progressive architectural remodeling of the vessel wall. Recent studies have focused on the role of matrix metalloproteinases (MMPs) in the pathogenesis of VVs. Aim of Study: The present study was assigned to demon-strate the morphologic and morphometric changes in the wall of VVs and to correlate these changes with the expression of MMP-1 and MMP-9. Material and Methods: A total number of 18 human long saphenous vein samples (8 normal and 10 VVs) were included in the study. The specimens were processed and examined histologically using hematoxylin and eosin, Masson's trichrome and orcein, together with immunohistochemistry for alpha smooth muscle actin (Eo-SMA). The mRNA expression of MMP-1 and MMP-9 was analyzed using real-time polymerase chain reaction (PCR). Quantitative morphometric measure-ments were carried out by the image analyzer. Results: The wall of VVs showed damaged endothelial surface, interrupted internal elastic lamina and numerous vasa vasora. There was significant increase in intima and media thickness compared to normal veins. Significant increase in the mean collagen area percent and decrease in elastin area percent was also observed. The mean area percent of Eo-SMA immunostaining and count of smooth muscle cells (SMCs) showed significant increase, indicating SMCs hypertrophy and hyperplasia, while the optical density of Eo-SMA immu-nostaining decreased. These changes were associated with significant increase in mRNA expression of MMP-1 and MMP-9. Conclusion: Varicose veins showed marked disorganiza-tion in all components of the vessel wall (collagen, elastin and SMCs). The associated increase in mRNA expression of MMPs might be one of the molecular mechanisms underlying vascular remodeling.

Berberine alleviates monosodium glutamate induced postnatal metabolic disorders associated vascular endothelial dysfunction in newborn rats: possible role of matrix metalloproteinase-1

Excessive food additives Monosodium glutamate (MSG) results in metabolic disorders with increased Cardiovascular diseases CVD. We aimed to emphasise berberine (BBR) effect on MSG induced metabolic syndrome (MetS) and its associated endothelial dysfunction. Newborn rats were divided into control group, MSG group (4 mg/g) each other day for the first 14 days of life and MSG + BBR group that was given MSG then BBR in dose 150 mg/kg/day for 6 weeks. Body weight, food intake, systolic blood pressure, biochemical metabolic and oxidative stress markers were evaluated. Aortic tissue homogenate Endothelin −1 (ET-1) and matrix metalloproteinase −1 (MMP-1) assessment, in addition to histological and EM examination were done. Newborn rats MSG exposure results in typical adult life MetS and oxidative stress with significant increase in ET-1 and MMP-1with aortic vasculopathy. BBR significantly improved all the disturbed parameters; suppress increased body weight (BW), food intake (FI) and partly improved the aortic vasculopathy lesions, holding a promise for BBR as a defending agent against MSG metabolic and vascular disorders. HIGH LIGHT MSG MSG is frequently consumed as a flavour enhancer especially between children and adolescent Excessive utilisation MSG is associated MS with vascular endothelial dysfunction MMP-1 may be involved in atherosclerotic plaque formation BBR has beneficial outcome for metabolic disorders induced by MSG among newly born rats BBR has a role in management vascular inflammation and remodelling

MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling.

Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix. Eight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817. MMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.

Regulation of Myocardial Extracellular Matrix Dynamic Changes in Myocardial Infarction and Postinfarct Remodeling.

The article represents literature review dedicated to molecular and cellular mechanisms underlying clinical manifestations and outcomes of acute myocardial infarction. Extracellular matrix adaptive changes are described in detail as one of the most important factors contributing to healing of damaged myocardium and post-infarction cardiac remodeling. Extracellular matrix is reviewed as dynamic constantly remodeling structure that plays a pivotal role in myocardial repair. The role of matrix metalloproteinases and their tissue inhibitors in fragmentation and degradation of extracellular matrix as well as in myocardium healing is discussed. This review provides current information about fibroblasts activity, the role of growth factors, particularly transforming growth factor β and cardiotrophin-1, colony-stimulating factors, adipokines and gastrointestinal hormones, various matricellular proteins. In conclusion considering the fact that dynamic transformation of extracellular matrix after myocardial ischemic damage plays a pivotal role in myocardial infarction outcomes and prognosis, we suggest a high importance of further investigation of mechanisms underlying extracellular matrix remodeling and cell-matrix interactions in cardiovascular diseases.