cathepsin-g and Myocardial-Infarction

Patients having experienced the ischemia-reperfusion process are particularly vulnerable to subsequent heart attacks because this process can induce myocardial fibrosis, hallmarked by the release of reactive oxygen species and some proteases, such as cathepsin G, into the circulating blood. If these risk indicators can be monitored from the peripheral serum, early diagnosis and intervention may become a reality. For this purpose, we have designed an assay of free copper ions and cathepsin G in serum using only synthetic small molecules as the biosensing elements. No antibodies are needed to recognize the target protein, and no enzymes are needed to generate and amplify the biosensing signal. In this design, a short peptide can target-specifically recognize protease, while the copper ion in the serum can stimulate the photoelectrochemical activity of the probe, resulting in cross-linking of the serum proteins in a target protein-specific manner. Using this method, serum cathepsin G and free copper ion are found to be significantly elevated in the blood samples collected from patients with acute myocardial infarction and successful percutaneous coronary intervention in comparison with healthy controls, indicating a higher risk of subsequent myocardial injury and cardiovascular events. These results may point to the possible application of the proposed assay to evaluate the severity and prognosis of cardiac ischemia/reperfusion in the near future.

Topics: Cathepsin G; Copper; Humans; Ions; Myocardial Infarction; Peptides; Reperfusion

A previous clinical study revealed elevation of chymase- and cathepsin G-dependent angiotensin II-forming activity (AIIFA) in the myocardium after acute myocardial infarction (AMI). This study examined the time course of chymase- and cathepsin G-dependent AIIFA in circulating mononuclear leukocytes (CML) after AMI. Consecutive patients with AMI were recruited. Chymase- and cathepsin G-dependent AIIFA in CML were assayed using a modified angiotensin I substrate with Nma/Dnp fluorescence quenching. The changes of CML AIIFA were monitored over time in the patients. Fifteen consecutive AMI patients admitted to our hospital were recruited. At 1 day after the admission, CML chymase- and cathepsin G-dependent AIIFA were 2.9- and 1.7-fold higher than at discharge, respectively. The ratio of chymase-dependent AIIFA to total AIIFA was significantly increased. AIIFA gradually decreased over time after the admission. The peak value of chymase- and cathepsin G-dependent AIIFA was significantly correlated with the maximum levels of aspartate aminotransferase (r = 0.53, 0.64), lactate dehydrogenase (r = 0.57, 0.62), and creatine kinase (r = 0.60, 0.65). This is the first evidence that chymase- and cathepsin G-dependent AIIFA is elevated in CML after AMI. Our data suggested that chymase-dependent AIIFA is increased in CML as well as in the myocardium after AMI, and that the level of chymase-dependent AIIFA might reflect the severity of infarction.

Topics: Aged; Angiotensin II; Cathepsin G; Chymases; Cross-Sectional Studies; Female; Humans; Japan; Male; Middle Aged; Myocardial Infarction; Myocardium; Percutaneous Coronary Intervention

There are indications that acute myocardial infarction (AMI) may have an effect on the oral environment, which is reflected in the expression of salivary and gingival proteinases. According to our knowledge, no studies have been carried out to investigate the effect of AMI on the activities of two major tissue-destructive serine protease and microbial effectors, elastase and cathepsin G, produced by oral fluid polymorphonuclear granulocytes (PMN). Therefore, we compared the activities of elastase and cathepsin G in saliva from patients with AMI and from systemically healthy subjects (non-AMI) with similar periodontal conditions.. A total of 92 patients (47 AMI and 28 non-AMI patients with gingivitis or periodontitis, and 17 systemically and periodontally healthy subjects as a control group) were recruited. Clinical periodontal measurements were recorded, and stimulated whole-saliva samples were collected. The patients with AMI were clinically examined within 3-4 d after admission to the coronary care unit. The activities of saliva neutrophil elastase and cathepsin G were measured after collection, at specific time-points during incubation (from baseline to 23 h) by specific synthetic peptide substrate assays.. The saliva of patients with AMI and periodontitis had a significant trend for the highest elastase activities among the study groups. Elastase and cathepsin G activities correlated significantly with each other in the AMI periodontitis group (r = 0.8, p < 0.01). In a logistic regression analysis, the level of salivary elastase activity associated significantly with periodontitis.. AMI may be reflected in PMN serine protease elastase activity in saliva, despite its strong association with periodontitis.

Topics: Adult; Aged; Cathepsin G; Chronic Periodontitis; Female; Follow-Up Studies; Gingival Hemorrhage; Gingivitis; Humans; Leukocyte Elastase; Male; Middle Aged; Myocardial Infarction; Periodontal Pocket; Periodontitis; Saliva; Salivary Proteins and Peptides; Tooth Loss

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Cathepsin G; Fibrin; Immunity, Innate; Leukocyte Elastase; Lipoproteins; Mice; Mice, Knockout; Models, Biological; Myocardial Infarction; Neutrophils; Nucleosomes; Protein Processing, Post-Translational; Serine Proteases; Signal Transduction; Stroke

Coronary heart disease (CHD) is a major killer worldwide. Atherosclerosis, which is the basis of CHD, is believed to be an inflammatory disorder. Though various aspects of atherosclerosis are extensively studied, leukocytic hydrolytic enzymes are not studied very well with respect to CHD.. This study was planned to assess changes associated with leukocytic hydrolases in CHD patients.. A tertiary care hospital; case-control study.. 106 patients with acute myocardial infarction, 60 patients with unstable angina and 45 healthy controls were included in the study. Acid phosphatase, lysozyme, adenosine deaminase (ADA) and cathepsin-G levels were estimated from leukocytes. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were measured.. Statistical comparison of data was done using student's t-test (unpaired). Correlation difference was calculated by using Pearson correlation coefficient.. Significantly higher levels of acid phosphatase, lysozyme, ADA with lower levels of cathepsin G in leukocytes were observed in CHD group. We also found significantly higher levels of serum MDA with lower concentrations of blood GSH in CHD group. In diabetic CHD group, significantly higher levels of leukocytic acid phosphatase, lysozyme, ADA and serum MDA with lower levels of cathepsin G and blood GSH were observed.. Our study indicates that leukocyte hydrolytic enzymes, mainly acid phosphatase, lysozyme and ADA were more active in CHD patients and may contribute to inflammation related with CHD. Its also indicates that leukocyte cathepsin-G may have antiinflammatory role.

Topics: Acid Phosphatase; Acute Disease; Adult; Angina, Unstable; Cathepsin G; Cathepsins; Coronary Disease; Female; Humans; Leukocytes; Male; Malondialdehyde; Middle Aged; Muramidase; Myocardial Infarction; Serine Endopeptidases

Cathepsin G (CTSG), a serine protease released from activated neutrophils, may cause platelet activation, leading to intravascular thrombosis, thus contributing to cardiovascular and cerebrovascular disease. Applying the candidate gene approach, we screened the 5'-flanking region and the entire coding region of the CTSG gene for genetic variation by using polymerase chain reaction/single-strand conformation polymorphism analysis from 96 patients at high risk for myocardial infarction (MI). We identified 4 polymorphisms in the 5'-flanking region (G-618C, G-315A, C-179T, and C-160T) and 1 polymorphism in the coding region (Asn125Ser) of the gene and genotyped the participants in the Etude Cas-Temoins sur l'Infarctus du Myocarde (ECTIM Study), a case-control study for MI, and in the Etude du Profil Génétique de l'Infarctus Cérébral (GENIC Study), a case-control study for brain infarction (BI), for all identified genetic variants. The potential in vitro functionality of the 4 variants in the 5'-flanking region was investigated with transient transfection analyses in U937 cells with different allelic promoter constructs by using a luciferase assay. Our in vitro analyses did not reveal any differences for the investigated allelic constructs with respect to promoter activity, and none of the polymorphisms in the 5'-flanking region was associated with the available phenotypes in either study. Allele and genotype distributions of all identified polymorphisms did not globally differ between cases and controls in the ECTIM Study. However, in patients from the ECTIM Study, the Ser125 allele was significantly associated with elevated plasma fibrinogen levels (P=0.006), but this effect was not seen in controls (case-control heterogeneity, P=0.04). There was a significant interaction between CTSG Asn125Ser and the beta-fibrinogen gene polymorphism G-455A on plasma fibrinogen levels (P=0.04). In the GENIC Study, the odds ratio for BI associated with CTSG Ser125 carrying was 1.82 (95% CI 1.16 to 2.84, P=0.008) in patients without a history of cardiovascular or cerebrovascular diseases. Our results indicate that the CTSG Ser125 allele is associated with plasma fibrinogen levels in MI patients from the ECTIM Study and with BI in the GENIC Study. Further studies should be carried out to define the underlying mechanisms.

Topics: Adult; Aged; Brain Infarction; Case-Control Studies; Cathepsin G; Cathepsins; Female; Fibrinogen; Gene Frequency; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Promoter Regions, Genetic; Serine Endopeptidases; Transcriptional Activation; Tumor Cells, Cultured

Topics: Cathepsin G; Cathepsins; Creatine Kinase; Humans; Infant; Leukocyte Elastase; Myocardial Infarction; Myocardium; Neutrophils; Pancreatic Elastase; Serine Endopeptidases

Myocardial extracellular matrix is organized into a complex arrangement of intercellular and pericellular fibres and fibrils that serves as a supporting framework for contracting cells. Recent evidence suggests that changes in ventricular shape and function occurring after ischaemic injury may be related to alterations of this matrix. In this report we describe the rapid and extensive loss of collagen in myocardial infarction produced by ligating the left anterior descending coronary artery of the rat for 1-3 h. The total collagen content in the myocardial infarct zones after 1, 2 and 3 h of ligation was 75 +/- 8%, 65 +/- 7% and 50 +/- 10% respectively (mean +/- S.D.) of that of either the non-infarcted tissue controls or of the same regions in sex- and age-matched normal left ventricles. A marked decrease also occurred in the residual collagens which were not extractable with 6 M-guanidine hydrochloride, suggesting that rapid degradation of insoluble collagen fibres may also occur. The decreased collagen content in the 3 h myocardial infarct coincided with the appearance of several enzyme activities. Collagenase, other neutral proteinase and presumed lysosomal serine proteinase activities were increased by 3, 3 and 2 times the control values respectively. These results suggest that the increased activities of collagenase and other neutral proteinases may be responsible for the rapid degradation of extracellular matrix collagen in myocardial infarct.

Topics: Animals; Autoradiography; Cathepsin D; Cathepsin G; Cathepsins; Collagen; Coronary Disease; Cross Reactions; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Hexosaminidases; Microbial Collagenase; Myocardial Infarction; Myocardium; Pancreatic Elastase; Rats; Rats, Inbred F344; Rats, Inbred Strains; Serine Endopeptidases