Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte-colony stimulating factor (G-CSF) has been reported to mobilize bone marrow multi-potent stem cells, which differentiate into cardiac myocytes after myocardial infarction (MI). However, there have not been any reports regarding the effect of G-CSF on stem cell infiltration in the MI site. Hearts of mice that had undergone coronary occlusion were isolated and digested with collagenase. Infiltrating cells in the heart were collected using Percoll density gradients. The infiltrating cells were sorted for side population (SP) cells using Hoechst 33342 dye. Hundreds of infiltrating SP cells were found in the heart from 1 to 14 d after MI. There were only a few SP cells in hearts without infarction. Infiltrating SP cells were increased in the 4-d G-CSF treated group compared with the vehicle group (1106 +/- 106 vs. 323 +/- 26/heart, P < 0.05). The infiltration of inflammatory cells was not influenced by the G-CSF treatment. In a separate series of experiments, we confirmed that the infiltrating SP cells were derived from bone marrow. That is, SP cells in the infarcted hearts of mice, which had been transplanted with bone marrow from ROSA 26 (beta-galactosidase transgenic) mice, were positive for beta-galactosidase. In the immunohistochemical examination, Sca-1(+)/CD45(-) cells were existed in the infarcted site after MI. Therefore, SP cells may infiltrate into infarcted heart. G-CSF augmented this kind of stem cell infiltration without increasing inflammatory cells. These results suggest that G-CSF may enhance myocardial regeneration without aggravated inflammation in the infarcted heart.
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PMID:G-CSF treatment increases side population cell infiltration after myocardial infarction in mice. 1513 66

Left ventricular (LV) remodeling following myocardial infarction (MI) is a complex process involving extracellular matrix degradation and fibrosis. While early remodeling is beneficial, chronic remodeling leads to decompensated heart failure (HF). We assessed the hypothesis that activation of the plasminogen-MMP system is involved in the remodeling of the infarct scar and compared it to the remaining viable myocardium. MI was induced by coronary artery ligature in 42 male Wistar rats. Three months following surgery, animals were divided into compensated (n=26) or decompensated (n=16) groups and compared to sham-operated rats (n=17). Scar and remaining viable LV myocardium (LVM) were separately analyzed for MMP-2, -7, -9, urokinase type and tissue type plasminogen activator (uPA and tPA) mRNA levels by RT-PCR. Their protein or activity levels, plus those of plasminogen/plasmin, tissue inhibitor of metalloproteinase-1, -2, -4 (TIMP-1, -2, -4) and plasminogen activator inhibitor-1 (PAI-1) were analyzed in tissue conditioned media by Western blot, ELISA and/or zymography. MMP and plasmin proteolytic activities were increased in the scar as compared to paired LVM thus indicating that activation of plasminogen and pro-MMPs is a key event in scar tissue remodeling. MMP and plasminogen activators (uPA, tPA) mRNAs were increased accordingly. Furthermore, inhibitors of the proteolytic enzymes, TIMP-1 and PAI-1 were increased in the scars from failing hearts and LVM thus suggesting a dynamic interplay between proteolysis and its inhibitors. This study shows a high degree of activation of the MMP-plasminogen system and the balance with their inhibitors in the infarcted myocardium, and suggests that this activation participates more to the remodeling of the scar tissue than to the remaining myocardium.
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PMID:The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat. 1562 36

The extracellular matrix (ECM) is a dynamic microenvironment and a major contributor to the adverse ventricular remodelling that follows myocardial infarction (MI), via activation of both direct pro-fibrotic pathways and matrix metalloproteinases (MMPs) that enhance collagenase activity. Reactive fibrosis, i.e. deposition of ECM materials remote from the region of the MI is clearly detrimental to ventricular function and contributory to adverse outcomes post-MI. Therefore, reversal of this process represents an important therapeutic target in post-MI management and treatment of established heart failure. A number of existing agents exert their beneficial effects in part via reductions in ECM deposition. Furthermore, specific anti-fibrotic drugs have been developed and are currently being explored for these and other cardiac conditions where pathological ECM deposition is felt to be contributory to disease progression.
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PMID:Fibrosis as a therapeutic target post-myocardial infarction. 1572 66

Following a severe ischemic injury or myocardial infarction, the extracellular matrix (ECM) of the heart is involved in pathophysiological conditions such as dilatation and cardiac dysfunction. Osteopontin (OPN) has been shown to interact with fibronectin suggesting its possible role in matrix organization, stability and wound healing. There is increased expression of OPN in several tissues in response to injury. Therefore, we tested the hypothesis that acute ischemia (2 h), followed by reperfusion (4 h) may induce early OPN and fibronectin in an isolated hemoperfused working porcine heart model. Twenty hearts were prepared and connected to a perfusion system. After 1 h of perfusion, these hearts were randomized to two groups: ten infarcted (MI, ramus circumflexus) and ten non-infarcted hearts (C). In addition, cardiac fibroblasts derived from infarcted, remote and control myocardium were investigated. In both groups, the heart rate, electrolytes, pH, blood gases, and lactate remained similar. The LVEDP and perfusion pressure of MI hearts increased significantly (P<0.05). The total fibronectin and OPN volume contents were clearly elevated in the infarct area. The matrix metalloproteinases (MMP-1 and MMP-8), fibronectin, OPN, TGF-beta1 proteins and the mRNAs for fibronectin, TGF-beta1, and OPN were significantly elevated in the infarct area as compared to the remote area and the non-infarcted hearts. Simultaneously, circulating carboxyterminal propeptide of type I procollagen (PICP) was released in the perfusion medium (threefold versus C). Fibroblast-like cells originating from the infarct area exhibited an enhanced OPN and fibronectin gene and protein expression compared to fibroblasts derived from control myocardium. Our data demonstrate the early appearance of the MMPs (increased collagen degrading enzymes) and PICP (a collagen synthesis marker) following ischemia and reperfusion. Moreover, OPN, fibronectin and TGF-beta1 protein and gene expression are elevated after ischemia and reperfusion in the ex vivo working hemoperfused porcine heart model.
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PMID:Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion. 1577 Apr 97

Some recent studies have demonstrated that epicardial injection of autologous myoblasts, obtained from satellite cells of skeletal muscle, in association to coronary artery bypass graft surgery (CABG) in patients with decreased left ventricular function secondary to ischaemic disease could be of some utility to get a better recovery of ventricular function due to the ability of these cells to grow and generate new muscle fibers over the previous fibrotic scar. The aims are the setting up of a process for the collection of the cellular cardiomyoplasty in samples of multiorganic donations and to carry out this technique in the same surgical moment as the revascularisation is performed in two patients. For this purpose we obtained muscle through biopsy of 15 human multiorgan donors and of two patients. Separation of fatty tissue, minced, and further digestion with collagenase type I (1.5 mgr/ml/2 gr by weight) and trypsin 1 x. Filtration of the cellular suspension, centrifugation and sowing of this suspension in culture medium, with 20% of human serum. Culture for three weeks until obtainment of between 200-300 million cells. Inmunohistochemistry and flow cytometry for the identification of the myoblasts was carried out. The results were obtained through flow cytometry, using CD56 as an indicator of the presence of myoblasts, between 70 and 80% of these types of cells were obtained after three weeks of culture. By inmunohistochemistry analyses, different markers were analyzed: desmin and myogenin. The results indicated the presence of a great number of positive cells with these markers, possibly myoblasts. Skeletal myoblast implant was not associated with adverse effects. The culture of autologous myoblasts is a rapid and simple technique where after three weeks of culture a great number of cells for implantation are obtained. In patients with old myocardial infarction, treatment with skeletal myoblast in conjunction with coronary artery bypass is safe and feasible. and it is easy to obtain myoblasts from muscle tissue for transplant into patients.
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PMID:Cellular cardiomyoplasty: development of a technique to culture human myoblasts for clinical transplantation. 1590 99

Lipid-rich atherosclerotic plaques are vulnerable, and their rupture can cause the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke. Although the role of plaque-based tissue factor as stimulator of blood coagulation has been recognized, it is not known whether plaques can cause thrombus formation through direct activation of platelets. We isolated lipid-rich atheromatous plaques from 60 patients with carotid stenosis and identified morphologically diverse collagen type I- and type III-positive structures in the plaques that directly stimulated adhesion, dense granule secretion, and aggregation of platelets in buffer, plasma, and blood. This material also elicited platelet-monocyte aggregation and platelet-dependent blood coagulation. Plaques exposed to flowing blood at arterial wall shear rate induced platelets to adhere to and spread on the collagenous structures, triggering subsequent thrombus formation. Plaque-induced platelet thrombus formation was observed in fully anticoagulated blood (i.e., in the absence of tissue factor-mediated coagulation). Mice platelets lacking glycoprotein VI (GPVI) were unable to adhere to atheromatous plaque or form thrombi. Human platelet thrombus formation onto plaques in flowing blood was completely blocked by GPVI inhibition with the antibody 10B12 but not affected by integrin alpha2beta1 inhibition with 6F1 mAb. Moreover, the initial platelet response, shape change, induced by plaque was blocked by GPVI inhibition but not with alpha2beta1 antagonists (6F1 mAb or GFOGER-GPP peptide). Pretreatment of plaques with collagenase or anti-collagen type I and anti-collagen type III antibodies abolished plaque-induced platelet activation. Our results indicate that morphologically diverse collagen type I- and collagen type III-containing structures in lipid-rich atherosclerotic plaques stimulate thrombus formation by activating platelet GPVI. This platelet collagen receptor, essential for plaque-induced thrombus formation, presents a promising new anti-thrombotic target for the prevention of ischemic cardiovascular diseases.
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PMID:Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI. 1592

Myocardial infarction (MI) is caused by occlusion of coronary artery and insufficient oxygen supply to a certain area of myocardium. Its necrosis appears as a result of MI. The process of tissue repair after MI is very complicated and it is influenced by numerous factors, including growth factors and proteolytic enzymes. The aim of the study was to determine serum transforming growth factor beta (TGF-beta) concentration on day 2 and 7 after MI and to asses the relationship of this growth factor with serum proteolytic activity of collagenase and elastase. In addition, the effect of fibrynolytic treatment on these factors was evaluated. About 100 patients with MI were enrolled to the study. The control group consisted of 50 healthy individuals. We observed that TGF-beta1 concentration correlated positively with collagenase activity on the second day after MI and that it also correlated positively with elastase activity on day 2 and 7 after MI. Moreover, treatment with streptokinase (SK) caused a significant increase of TGF-beta serum concentration. Our data indicate that TGF-beta1 may be one of the factors involved in tissue repair process after MI. Its effect seems to be mediated by collagenase and elastase and may change with the time that elapsed after MI.
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PMID:Proteolytic enzymes activities in patients after myocardial infarction correlate with serum concentration of TGF-beta. 1613 1

Human cartilage is reported to contain multipotent stromal cells. We evaluated the effect of human cartilage-derived stromal cells (CDSCs) on heart function when transplanted into the infarcted myocardium of rats. CDSCs were isolated and cultured from human articular cartilage and subjected to fluorescence-activated cell sorting (FACS) analysis. The CDSCs were consistently negative for CD14, CD34, CD38, CD45, CD49f, CD104, CD105, CD106, CD117, HLA-DR, and ABCG-2, and positive for CD10, CD44, CD71, CD73, CD90, CD147, and HLA-A, -B, and -C by FACS analysis. Myocardial infarction (MI) was created in rats by ligation of the left anterior descending artery. Three weeks after MI, the CDSCs labeled with Hoechst stain were injected into the infarct and border zone. Echocardiography, histological examination, and reverse transcription-polymerase chain reaction (RT-PCR) were performed 4 weeks after cell transplantation. Echocardiography indicated that CDSC transplantation could improve heart function. The number of capillaries increased in the injection regions in the transplantation group. Histological examination showed that Hoechst-labeled CDSCs in islands within the infarcted region were stained positively for desmin and smooth muscle actin but negatively for alpha-sarcomeric actin and troponin-I. RT-PCR results indicated the expression level of collagen I, collagen III, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta1, and vascular endothelia growth factor were much higher in the scar tissue in the transplantation group than in the medium and control groups. Our findings suggested that CDSCs might promote angiogenesis, prevent left ventricular remodeling, and improve the heart function when transplanted into injured heart in the rat model of myocardial infarction.
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PMID:Cartilage-derived stromal cells: is it a novel cell resource for cell therapy to regenerate infarcted myocardium? 1623 22

Clinical observations suggest that patients with coronary artery disease (CAD) display a marked heterogenerty in collateral formation despite similar degrees of coronary obstruction. The development of coronary collaterals helps protect the myocardium from ischemic damage, yet the factors responsible for collateral formation are poorly understood. To better understand the biochemical and cellular mechanisms of collateral artery formation, monocyte function and circulating levels of pro- and antiangiogenic factors were measured in 101 patients with angiographically assessed CAD and extensively developed (score 2, n = 33) or absent (score 0, n = 68) collateral circulations. Compared with patients with score 0, those with score 2 were slightly older and had more advanced CAD. The score 2 group was also more likely to have had a previous myocardial infarction or coronary artery bypass grafting and a family history of CAD. At the same time, there were no significant differences between groups with regard to circulating levels of vascular endothelial growth factor-A(165), platelet-derived growth factor-betabeta, fibroblast growth factor-2, fibroblast growth factor-4, hepatocyte growth factor, tumor necrosis factor-alpha, interleukin-1beta, endostatin, matrix metalloproteinase-9, promatrix metalloproteinase-1, and CD40 ligand. Monocytes isolated from patients with score 2 and 0 collateral circulations demonstrated no differences in migration assays. However, adhesion to fibrinogen and collagen was significantly higher for monocytes from patients with score 0 (p = 0.05 and 0.04, respectively). In conclusion, these data suggest that the degree of coronary collateral formation is not determined by differences in systemically measurable levels of pro- or antiangiogenic factors assessed in this study. Rather, cellular properties, such as cell adhesion, or genetic differences between patients may be the driving force for collateral development.
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PMID:Humoral and cellular factors responsible for coronary collateral formation. 1705 26

Despite the numerous advances made in the prevention and treatment of cardiovascular diseases, there is a need for new strategies to repair and/or regenerate the myocardium after ischemia and infarction in order to prevent maladaptive remodeling and cardiac dysfunction. This article compiles and analyzes the available experimental data regarding the potential therapeutic effects of thymosin-beta4 and its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in cardiac healing after myocardial infarction (MI) as well as discussing the possible mechanisms involved. The healing properties of thymosin-beta4 have been described in different types of tissues, such as the skin and cornea, and more recently it has been shown that thymosin-beta4 facilitates cardiac repair after infarction by promoting cell migration and myocyte survival. Additionally, the tetrapeptide Ac-SDKP was reported to reduce left ventricular fibrosis in hypertensive rats, reverse fibrosis and inflammation in rats with MI, and stimulate both in vitro and in vivo angiogenesis. Ac-SDKP also reduced cardiac rupture rate in mice post-MI. Some of the effects of Ac-SDKP, such as the enhancement of angiogenesis and the decrease in inflammation and collagenase activity, are similar to those described for thymosin-beta4. Thus, it is possible that Ac-SDKP could be mediating some of the beneficial effects of its precursor. Although the experimental evidence is very promising, there are no data available from a clinical trial supporting the use of thymosin-beta(4) or Ac-SDKP as means of healing the myocardium after MI in patients.
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PMID:Therapeutic potential of thymosin-beta4 and its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in cardiac healing after infarction. 1708 65


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