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)

The plasma concentration of lipoprotein (a) (Lp(a] varies widely in humans, and elevated concentrations of this lipoprotein are correlated with progression of atherosclerosis. Structural studies of Lp(a) have revealed that it is a low density lipoprotein (LDL)-like particle containing a unique glycoprotein, apo(a), which shares extensive homology with plasminogen. The apo(a) portion of Lp(a) binds to the carboxy-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) or isolated apo(a) with fibronectin results in proteolytic cleavage of fibronectin which is, as visualized by gel electrophoresis and immunoblotting, distinct from that caused by plasmin or kallikrein. The proteolytic activity of apo(a) is of serine proteinase-type and displays specificity for arginine rather than lysine bonds. The molecular mechanism(s) underlying the association between Lp(a) and atherosclerosis remains an enigma.
 ...
PMID:Interaction of lipoprotein(a) with fibronectin and its potential role in atherogenesis. 214 25

The main advances since 1980 in our understanding of atherosclerosis can be summarised under four headings. 1) The migration and proliferation of smooth muscle cells from the media into the intima are key-events of atherogenesis, and probably also of restenosis following percutaneous transluminal coronary angioplasty. The experimental study of their regulations, especially looking for inhibitors, has therefore gained increased interest as it may provide original approaches to the prevention of post-angioplasty restenosis. 2) The histiocytes/macrophages, derived from blood monocytes, also take a major part in the initiation of atherosclerotic lesions. An intensive research activity is now being devoted to elucidating the many facets of their participation in atherogenesis. 3) Brown and Goldstein's discoveries have explained the biochemical mechanisms of the increased plasma low-density lipoprotein (LDL) concentration found in familial hypercholesterolemia (type IIa), although they did not completely solve the enigma of lipid deposition in the arterial wall. The metabolic handling of modified LDLs appears to be crucial to the foamy transformation of macrophages and, possibly, of smooth muscle cells. 4) Risk factors identified by epidemiology are usually held responsible for atherosclerosis. Yet this causal interpretation is not entirely satisfactory, and alternative or complementary hypotheses are being but forward. Among them, the most consistent submits that a viral aggression of the arterial wall is involved in the genesis and progression of atherosclerosis.
 ...
PMID:[New concepts of atherogenesis]. 283 18

To better understand the putative association between insulin and atherosclerosis many experimental studies have explored the metabolic effects of insulin upon the arterial intima-media (which is essentially made up of smooth muscle cells). This tissue appears to be insulin-sensitive in vivo but not in vitro, suggesting that the actions of insulin on arterial metabolism are probably indirect. Yet, cultured arterial smooth muscle cells do increase their anabolism when physiological concentrations of insulin (10-250 microU/ml) are added to the medium. To account for these discrepancies we have proposed a haemodynamic explanation : hydrostatic forces present in vivo but absent in vitro, would be necessary for insulin to reach the cells of the media and act upon them. We demonstrated such an effect using an isolated rat aorta perfused under variable pressure. But only highly unphysiological concentrations of insulin (0.1 mU/ml) could stimulate the metabolism of intima-media significantly. The insulin-sensitivity of the target tissue for atherosclerosis remains an enigma. We speculate that the variable phenotype of arterial smooth muscle cells (either contractile or synthetic) might be an interesting clue to this problem.
 ...
PMID:Effects of insulin and hydrostatic forces on the metabolism of the aorta. 330 58

Occlusion of the internal carotid or middle cerebral artery was seen in 44 young adults of both sexes from a rural population in Ceylon over a period of four years. None had hypertension, diabetes, prediabetes, or hypercholesterolaemia. There were 19 men with internal carotid occlusions, most being due to atherosclerotic thrombosis. The high incidence of atherosclerosis in these patients on a marginal diet remains an enigma, and we suggest that carbohydrate-induced hyperlipidaemia might be an important aetiological factor. There were 13 men with middle cerebral occlusions, the aetiology of which remains obscure. Occult embolism or atherothrombosis are suggested as possible causative factors. Of the 12 women five had middle cerebral artery occlusions in the last trimester of pregnancy and two had internal carotid artery occlusions in the puerperium. The pattern of ischaemic strokes in women aged 15-45 was similar to that observed in Western countries, though our patients differed ethnologically and in dietary habits.
 ...
PMID:Strokes in young adults. 507 49

Atherosclerosis is the major cause of death in the industrialised world. Though much work on the pathogenesis of atherosclerosis points to 'oxidised' low density lipoprotein (LDL) as a key aetiological feature in the generation of the atherosclerotic plaque, the nature of this 'oxidised' LDL in vivo remains an enigma. We argue here that glycated LDL shows many of the characteristics attributed to 'oxidised LDL' and may be the source of the latter in vivo. These include the increased uptake and impaired degradation of glycated LDL by macrophages and the stimulation of transendothelial chemotaxis of monocytes, cytokine secretion and platelet aggregation. We hypothesise that the covalent binding of glycated LDL to the endothelial cell wall may result in the formation of the early atherosclerotic lesion of the fatty streak and that apolipoprotein E may mediate the physiological clearance of glycated moieties. The proposed role of glycation in the pathogenesis of atherosclerosis would explain its high incidence among diabetics and the contentious epidemiological and experimental correlations between dietary sugar and atherosclerosis.
 ...
PMID:Atherosclerosis and glycation. 814 45

Saphenous vein graft failure is one of the primary reasons for coronary artery bypass reoperation. The economic impact alone in this country is staggering in an era of intensive cost cutting. The fact that some vein grafts remain free of disease for years while the sibling vein develops extensive atherosclerosis remains an enigma. Saphenous vein valves have recently attracted interest. Repeated angiograms show that vein graft disease invariably is accentuated around valves. Studies show that the segment of saphenous vein distal to the valves have more accelerated and intense atherosclerosis. Early results of saphenous vein bypass grafting may be predicted with some degree of certainty by saphenous vein graft biopsy. Attention is now being turned to the hypercoagulable state as a cause of graft failure, as this has not been previously addressed. Research into pharmacologic agents for maintaining open grafts has had disappointing results and aspirin alone is still the single drug of choice to promote patency. Preparation of the graft continues to be important because there is direct evidence that surgical injury during preparation leads to neointimal thickening and vascular smooth muscle proliferation. Although there are some exciting new modalities for preventing graft disease, the difficulty in transposing animal data to humans and the uncertainty of the biologic similarities of in vitro and in vivo endothelial cell biochemistry makes any immediate solution unlikely. Therefore an even greater increase in the use of arterial grafts in the near future seems likely, even with their associated problems.
 ...
PMID:Vein graft failure. 857 75

The role of herpesvirus infections in the pathogenesis of vascular diseases remains an enigma. Although there is abundant circumstantial evidence of a role for herpesviruses in atherosclerosis and related processes, a cause-and-effect relationship has yet to be definitively established. This article will review the pathological, molecular, and biochemical evidence supporting the hypothesis that herpesviruses are involved in the development of atherosclerosis, restenosis after coronary angioplasty, accelerated atherosclerosis in recipients of heart transplants, and the induction of a prothrombotic phenotype in vascular endothelial cells.
 ...
PMID:Herpesvirus in atherosclerosis and thrombosis: etiologic agents or ubiquitous bystanders? 951 1

Why LDL entrapped in the subendothelium should trigger events leading to chronic inflammation and to arterial wall injury is a major enigma of modern medicine. Oxidation of LDL in vitro renders the molecule potentially atherogenic, and the concept that oxidation is the major single event underlying the transformation of LDL to a proinflammatory molecule dominates the world literature. Here, an alternative hypothesis on the pathogenesis of atherosclerosis will be presented. We have found that non-oxidative, enzymatic modification of LDL with ubiquitous enzymes (protease + cholesterol esterase + neuraminidase) also transforms the molecule to an atherogenic moiety. Enzymatically altered LDL (E-LDL) shares major properties in common with lipoproteins that have been isolated from atherosclerotic lesions. It activates complement via the alternative pathway and is recognized by a scavenger receptor on human macrophages, thus inducing foam cell formation. Uptake of E-LDL is accompanied by potent induction of MCP-1 synthesis and secretion. In contrast, E-LDL does not stimulate IL-1 or TNF-production and is only a weak inducer of IL-6. Monoclonal antibodies were produced that recognize neoepitopes on E-LDL, but that do not react with native or oxidized LDL. With the use of these antibodies, extensive deposition of E-LDL in very early atherosclerotic lesions was demonstrated. Activated complement components colocalized with E-LDL, corroborating the concept that subendothelially deposited LDL is enzymatically transformed to a complement activator at the earliest stages in lesion development. The pathogenetic relevance of unhalted complement activation in atherogenesis was demonstrated with the use of C6-deficient rabbits. It was found that C6-deficiency markedly protected against development of diet-induced atherosclerosis in the experimental animals. In sum, our hypothesis departs from the mainstream of atherosclerosis research and derives from the recognition that extracellular exposition of free cholesterol in LDL-particles by itself confers pro-inflammatory properties onto the lipoprotein molecule. We believe that the degrading enzymes are ubiquitously present in the extracellular matrix, so the only requirement for atherogenesis to occur is the deposition of large amounts of LDL. Oxidative processes or infections probably play only minor roles, and reduction of LDL plasma levels will predictably represent the single most important prophylactic measure against development and progression of atherosclerosis.
 ...
PMID:[An alternative hypothesis of the pathogenesis of atherosclerosis]. 964 97

The pathogenesis of autoimmune disease is still an enigma. Whereas the diverse clinical manifestations of many autoimmune diseases cannot be explained by the existence of autoantibodies, idiotypic dysregulation may provide an alternative explanation. Experimental models, serum level changes of pathogenic idiotypes during exacerbation and remission, and the increased expression of pathogenic idiotypes following common infections all support this notion. In this article we review experimental models of autoimmune disease induction (systemic lupus erythematosus, antiphospholipid syndrome, Goodpasture's syndrome, autoimmune thyroiditis, and vasculitis) by manipulation of the idiotypic network, and discuss the utilization of idiotypes for the immunotherapy of autoimmune diseases and other conditions that involve the immune system (e.g., atherosclerosis).
 ...
PMID:Idiotypic network dysregulation: a common etiopathogenesis of diverse autoimmune diseases. 1082 56

Dementia in the elderly used to be rare, but why has it become a major social threat today? There can be many potential answers, but an ultimate one is clear: the longer life expectancy today. This knowledge indicates that "advanced aging" is a primary suspect in the origin of senile dementia. If so, then why can many elderly remain healthy at the same old age? We know, for example, that elderly people commonly have a certain degree of atherosclerosis and osteoporosis, but only some of them develop severe clinical symptoms at the same age. These different outcomes generally can be explained by "risk factors" in life (exercise, diet, individual background, etc). It thus appears to be a general pattern that advanced aging (after age 80) will set the stage for various senile disorders, but risk factors largely determine the onset age as well as individual specificity of their clinical manifestations. In this context, senile disorders including senile dementia would differ fundamentally from the pathogen-caused conventional diseases (AIDS, polio, cancer, Down's, etc.) by origin, incidence, and intervention strategy. This view would call into question the current definition of senile dementia as a conventional "disease" (Alzheimer's). The term "Alzheimer's disease" originally referred to "midlife" dementia, but it is defined today to be the same medical entity as senile dementia on the basis that they both display the same hallmarks and symptoms despite their onset age difference. Now, after in-depth scrutiny, we finally come to realize that they are not the same disease, but as different as heart failure at midlife versus the "same" failure at advanced age (i.e., a conventional disease versus a senile condition). Thus, by eliminating the age difference, the new definition has converted a senile condition into a conventional "disease", thereby changing the course of its scientific inquiry to miss the main targets. This may be why after extensive studies for 25 years, the origin of senile dementia has remained an enigma.
 ...
PMID:Alzheimer movement re-examined 25 years later: is it a "disease" or a senile condition in medical nature? 1150 85


1 2 Next >>