Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein(a) [apo(a)] is a glycoprotein with Mr approximately equal to 280,000 that is disulfide linked to apolipoprotein B in lipoprotein(a) particles. Elevated plasma levels of lipoprotein(a) are correlated with atherosclerosis. Partial amino acid sequence of apo(a) shows that it has striking homology to plasminogen. Plasminogen is a plasma serine protease zymogen that consists of five homologous and tandemly repeated domains called kringles and a trypsin-like protease domain. The amino-terminal sequence obtained for apo(a) is homologous to the beginning of kringle 4 but not the amino terminus of plasminogen. Apo(a) was subjected to limited proteolysis by trypsin or V8 protease, and fragments generated were isolated and sequenced. Sequences obtained from several of these fragments are highly (77-100%) homologous to plasminogen residues 391-421, which reside within kringle 4. Analysis of these internal apo(a) sequences revealed that apo(a) may contain at least two kringle 4-like domains. A sequence obtained from another tryptic fragment also shows homology to the end of kringle 4 and the beginning of kringle 5. Sequence data obtained from two tryptic fragments show homology with the protease domain of plasminogen. One of these sequences is homologous to the sequences surrounding the activation site of plasminogen. Plasminogen is activated by the cleavage of a specific arginine residue by urokinase and tissue plasminogen activator; however, the corresponding site in apo(a) is a serine that would not be cleaved by tissue plasminogen activator or urokinase. Using a plasmin-specific assay, no proteolytic activity could be demonstrated for lipoprotein(a) particles. These results suggest that apo(a) contains kringle-like domains and an inactive protease domain.
 ...
PMID:Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. 347 6

Many human atherosclerotic lesions, showing no evidence of fissure or ulceration, contain a large amount of fibrin which may be in the form of mural thrombus on the intact surface of the plaque, in layers within the fibrous cap, in the lipid-rich centre, or diffusely distributed throughout the plaque. Small mural thrombi are invaded by SMCs and collagen is deposited in patterns closely resembling the early proliferative gelatinous lesions. In experimental animals, thrombi are converted into lesions with all the characteristics of fibrous plaques, and in saphenous-vein bypass grafts, fibrin deposition is the main cause of wall thickening and occlusion. There seems little doubt that fibrin deposition can both initiate atherogenesis and contribute to the growth of plaques. Epidemiological studies indicate that increased levels of fibrinogen and clotting activity are associated with accelerated atherosclerosis, and although blood fibrinolytic activity has given inconsistent results, in arterial intima both fibrinolytic activity and plasminogen concentration are decreased in cardiovascular disease. Fibrin may stimulate cell proliferation by providing a scaffold along which cells migrate, and by binding fibronectin, which stimulates cell migration and adhesion. Fibrin degradation products, which are present in the intima, may stimulate mitogenesis and collagen synthesis, attract leukocytes, and alter endothelial permeability and vascular tone. In the advanced plaque fibrin may be involved in the tight binding of LDL and accumulation of lipid. Thus there is extensive evidence that enhanced blood coagulation is a risk factor not only for thrombotic occlusion, but also for atherogenesis. Enhanced blood coagulation frequently coexists with hyperlipidaemia and, together, these may have a synergistic effect on atherogenesis.
 ...
PMID:Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis. 352 31

Lipoprotein(a) is an LDL-like lipoprotein whose concentration in plasma is correlated with atherosclerosis. The characteristic protein component of lipoprotein(a) is apolipoprotein(a) which is disulphide-linked to apolipoprotein B-100. Sequencing of cloned human apolipoprotein(a) complementary DNA shows that it is very similar to human plasminogen. It contains a serine protease domain and two types of plasminogen-like kringle domains, one of which is present in 37 copies.
 ...
PMID:cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. 367 Apr

In samples of human aortic intima fibrin/fibrinogen degradation products (FDP) were assayed by isoelectric focussing/immunoelectrophoresis as a possible measure of endogenous fibrinolysis, and plasminogen concentration was assayed by rocket immunoelectrophoresis as a possible marker for fibrinolytic potential. No consistent differences were found between normal intima and different types of atherosclerotic lesion, but there was marked variation between patients, and multiple samples from the same aorta showed similar levels. There was no significant correlation with age, sex, or time after death. Low concentrations of FDP and failure to recover measureable amounts of plasminogen from intima were highly associated with death in patients who had suffered a recent myocardial infarction. In aortas from which 3 or more samples of intima and lesions were obtained (n = 16), no FDP were found in 3 (total of 12 samples); all of these were from patients who died following myocardial infarction. Low levels were present in the 4th patient with myocardial infarction. No plasminogen was found in 10 of 11 aortas from patients dying after myocardial infarction (total of 46 samples with no plasminogen), but it was present in 10 of 17 aortas from patients dying of other causes (X2 = 7.6, P less than 0.01). Where both were assayed, FDP were not found in any samples which did not contain plasminogen. Low levels of FDP and absence of plasminogen were associated with increased involvement with atherosclerosis. There was no relation between intimal and serum plasminogen levels, and prothrombin and low density lipoprotein were present in all samples from which no plasminogen was recovered. The results indicate that in some patients, particularly those dying after myocardial infarction, there is decreased fibrinolysis and fibrinolytic potential in the arterial intima, and this may result in increased intimal accumulation of fibrin.
Atherosclerosis 1985 May
PMID:Fibrinolysis and plasminogen concentration in aortic intima in relation to death following myocardial infarction. 400 89

Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.
 ...
PMID:Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture. 645 Feb 58

Fibrin contains a factor which promotes growth of the mesenchymal cells and such may be related tissue repair. Effects of fibrin and fibrinogen degradation products (FDP) on the growth of smooth muscle cells (SMC) of rabbit aortas in culture were investigated, in relation to atherogenesis. Fibrin, free from plasminogen enhanced the proliferation of SMC during the experimental period of 48 h. Fibrin, rich in plasminogen also stimulated the proliferation of SMC within 24 h, but inhibited it after 48 h. FDP (fragments D and E) inhibited the proliferation of SMC. SMC of rabbit aortas demonstrated plasminogen activator activity. Thrombin and urokinase exhibited no promoting effects on the growth of SMC. These results support the hypothesis that the proliferation of SMC is stimulated by fibrin and later inhibited by FDP, as produced by the fibrinolytic activity of SMC. It is proposed that the metabolism of fibrin in the arterial wall may be of importance in the regulation of SMC proliferation and that the coagulation-fibrinolysis system may play a significant role in atherogenesis.
Atherosclerosis 1982 Aug
PMID:Effects of fibrin and fibrinogen-degradation products on the growth of rabbit aortic smooth muscle cells in culture. 713 18

Lipoprotein (a) is a relatively new independent risk factor of early atherosclerosis with atherogenic and thrombogenic properties. From the structural aspect it resembles LDL-lipoprotein and differs from the latter by the presence of another glycoprotein-apolipoprotein (a). Due to the great similarity of apolipoprotein (a) and plasminogen, lipoprotein (a) is bound to plasminogen receptors on the fibrin surface (fibrinogen) and thus prevents the cumulation and activation of local fibrinolysis. Its levels are under strict genetic control and are very little influenced by external factors and available hypolipidaemic treatment. There is a great interindividual variability of lipoprotein(a) concentrations which is due above all to the structural variability of apolipoprotein (a). At present at least 34 isoforms of apolipoprotein(a) were described which differ as to the size of the molecule. This great structural variability has an impact not only on the function and pathogenicity of lipoprotein (a) but also on methods of its assessment. High lipoprotein(a) concentrations are found in subjects with early clinical manifestations of atherosclerosis, in nephrotic syndrome, in chronic renal insufficiency, in haemodialyzed patients and other diseases. They rise in women after the menopause and are favourably influenced by hormonal substitution therapy. There is a number of immunochemical methods used for its estimation which are very well reproducible within the same laboratory. The high interlaboratory coefficients of variation indicate, however, that unification of lipoprotein(a) analyses is urgent.
 ...
PMID:[Lipoprotein (a): a genetic risk factor with atherogenic and thrombogenic properties]. 748 54

Atherosclerosis is the leading cause of death and serious morbidity in economically developed societies through its sequelae of coronary artery and cerebrovascular disease. The causes and mechanisms of atherosclerosis are still largely unknown. Serum levels of a lipoprotein, Lp(a), have been shown, in retrospective and some prospective clinical studies, to be associated with increased risk of myocardial and cerebral infarction. The active part of Lp(a), apo(a), has > 80% homology with plasminogen; thus it may competitively inhibit the thrombolytic action of plasminogen and enhance thrombogenesis. Lp(a) has been shown to be deposited in the vascular wall of the aorta and coronary vessels, but its presence in the cerebral vessels has not yet been shown. Autopsy specimens of vessels of the circle of Willis from 23 patients were examined for degree of atherosclerosis and deposition of apo(a) by immunohistochemistry with apo(a)-specific monoclonal antibodies. The amount of apo(a) deposition in cerebral vessels correlated well with the degree of cerebral atherosclerosis. Arterial deposition of apo(a) was found entirely within the endothelial cell and subendothelial cell layers. There was no staining within the media and adventitia, with the exception of staining within the endothelial cells of the vasa vasorum. Correlation between the morphology of apo(a) deposition and plaque stage was found suggesting that detection of apo(a) in endothelial cells is an early event in the development of the atherosclerotic plaque of cerebral vessels.
 ...
PMID:Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation. 749 81

Studies with transgenic mice over- or under-expressing components of the fibrinolytic system, have revealed a significant role of this system in fibrin clot surveillance, reproduction, (vascular) wound healing, brain function, health and survival. The distinct phenotypes associated with single loss and the more severe phenotype associated with combined loss of plasminogen activator gene function suggest that through evolution, both plasminogen activators have evolved with specific but overlapping biological properties. Interestingly, the role of the fibrinolytic system in thrombosis and vascular wound healing became more apparent after challenging mice single deficiencies of plasminogen activators with an inflammatory, or traumatic challenge, respectively. It therefore seems warranted to examine possible consequences of loss of plasminogen activator gene function in other processes including atherosclerosis, neoangiogenesis, inflammatory lung and kidney disease and malignancy. The plasminogen activator knock-out mice with their thrombotic phenotypes are also valuable models to evaluate whether adenoviral mediated gene-transfer of wild-type or mutant plasminogen activator genes is able to restore normal thrombolytic function and to prevent thrombosis. Preliminary evidence suggests that impaired thrombolysis of t-PA deficient mice can be completely restored using adenoviral-mediated gene transfer of rt-PA (Carmeliet et al, 1994c). In addition, analysis of neointima formation in plasminogen activator deficient mice suggests that controlled reduction of fibrinolytic activity in the vessel wall might be beneficial for the prevention or reduction of restenosis. Whether this can be achieved with gene transfer methodologies remains to be defined.
 ...
PMID:Physiological consequences of over- or under-expression of fibrinolytic system components in transgenic mice. 754 69

A wide variety of haemostatic variables were measured in healthy male subjects predominantly blood donors residing in Riyadh, the capital city of Saudi Arabia. Subjects were divided according to ethnic origin: Saudi Arabs n = 487, Westerners (Europeans and Americans) n = 300, South East Asians (Koreans and Filipinos) n = 360, and West Africans n = 82. There were no significant differences in prothrombin time, partial thromboplastin time, thrombin time, reptilase time, plasma fibrinogen, antithrombin, plasminogen and platelet count between Saudis, Westerners and Asians. Africans exhibited significantly lower plasma levels of fibrinogen, platelet count and plasminogen than other ethnic groups. Arabs and Africans had higher levels of FVIII:C and vWF:ristocetin cofactor than Westerners. On the other hand, FX was significantly higher in Westerners than in other ethnic groups. Smokers had higher fibrinogen levels than non-smokers. These variations, which could not be related to blood group distribution, physical parameters of height and weight, may be due to genetic and/or dietary habits. In conclusion, this study established the existence of racially determined variations in haemostatic variables, with Black Africans showing changes consistent with a lesser tendency towards atherosclerosis and cardiovascular disease than other ethnic groups. These variations should be taken into account when investigating the haemostatic system in patients.
 ...
PMID:Ethnic variations in the haemostatic system: comparison between Arabs, Westerners (Europeans and Americans), Asians and Africans. 757 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>