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)

Oxidation of low-density lipoprotein (LDL) is thought to be a major factor in the pathophysiology of atherosclerosis. Elevated plasma homocysteine is an accepted risk factor for atherosclerosis, and may act through LDL oxidation, although this is controversial. In this study, homocysteine at physiological concentrations is shown to act as a pro-oxidant for three stages of copper-mediated LDL oxidation (initiation, conjugated diene formation and aldehyde formation), whereas at high concentration, it acts as an antioxidant. The affinity for copper of homocysteine and related copper ligands homocysteine, cystathionine and djenkolate was measured, showing that at high concentrations (100 microM) under our assay conditions, they bind essentially all of the copper present. This is used to rationalise the behaviour of these ligands, which stimulate LDL oxidation at low concentration but generally inhibit it at high concentration. Albumin strongly reduced the effect of homocystine on lag time for LDL oxidation, suggesting that the effects of homocystine are due to copper binding. In contrast, copper binding does not fully explain the pro-oxidant behaviour of low concentrations of homocysteine towards LDL, which appears in part at least to be due to stimulation of free radical production. The likely role of homocysteine in LDL oxidation in vivo is discussed in the light of these results.
 ...
PMID:Copper-mediated LDL oxidation by homocysteine and related compounds depends largely on copper ligation. 1473 79

Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify Abeta, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.
 ...
PMID:Metabolite-initiated protein misfolding may trigger Alzheimer's disease. 1503 69

Acetylcholine esterase (AChE) and paraoxonase 1 (PON1) are both serum ester hydrolases, which are associated with the prevalence of myocardial infarction. Both genes are located in close proximity on chromosome 7q21-22. As PON1 was suggested to protect against cardiovascular diseases secondary to its ability to break down oxidized lipids and to inhibit LDL oxidation, we examined AChE capacity to protect LDL against oxidation. Preincubation of LDL with AChE retarded the onset of copper ion-induced LDL oxidation in a concentration-dependent manner. AChE significantly reduced the formation of lipid peroxides and TBARS during the course of LDL oxidation, by up to 45%. This effect was associated with AChE-mediated hydrolysis of lipid peroxides, which accounts for the inhibition in the onset of LDL oxidation, the oxidative propagation phase, and aldehyde formation. We conclude that AChE, similar to PON1, can hydrolyze lipid peroxides and thus may prevent the accumulation of oxidized LDL and attenuate atherosclerosis development.
 ...
PMID:Acetylcholine esterase protects LDL against oxidation. 1533 59

Fatty aldehyde dimethyl acetals (DMA) derived from plasma and erythrocyte membrane plasmalogen phospholipids of 109 donors, aged 25-91 years, were measured as weight percent of total phospholipid fatty acids and DMA. The age range from 70 to 90 years (n = 82) was divided into age groups of five years each. Cumulative distributions of the DMA values of these age groups, when compared with those of 17 younger persons (aged 25-41 years), revealed a tendency to higher DMA values in the youngest age group, and to lower values in the oldest one. Linear regressions were computed between age and hexadecanaldimethylacetal (16:0 DMA) or octadecanaldimethylactal (18:0 DMA) of erythrocyte membrane and plasma phospholipids. Statistically significant negative correlations with age were obtained. Because of their sensitivity to oxidation reactions, a role of plasmalogens as a natural antioxidant in oxidative defense mechanisms appears to be convincing. However, it will possibly be difficult to separate the effects of normal aging on the decline of plasmalogen phospholipid levels in some tissues from those of certain pathological conditions - including hyperlipidemia and atherosclerosis.
 ...
PMID:Plasmalogen phospholipids - facts and theses to their antioxidative qualities. 1537 2

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in a variety of environment situations and is also a product of lipid peroxidation. Increased unsaturated aldehyde levels and reduced antioxidant status play an important role in the pathogenesis of a number of human diseases such as Alzheimer's, atherosclerosis, and diabetes. Mammalian thioredoxin reductase (TR), a central antioxidant enzyme, is a selenoprotein that catalyzes the reduction of oxidized thioredoxin. The findings reported here show that low concentrations of acrolein rapidly inactivate TR, both in vitro and in vivo. These data suggest that acrolein may directly inactivate TR, resulting in an increase in oxidative cellular damage. In addition, we also found that the initial inactivation of TR molecules by acrolein triggers a compensatory signal for inducing TR gene expression in human umbilical vein endothelial cells (HUVEC). The results of the present study suggest that HUVEC may have a protective system against cell damage by acrolein via the upregulation of TR, which is an adaptive response to oxidative stress.
 ...
PMID:Induction of thioredoxin reductase as an adaptive response to acrolein in human umbilical vein endothelial cells. 1565 4

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.
 ...
PMID:Oxidative stress in atherosclerosis and diabetes. 1625 16

4-Hydroxynonenal (HNE) is by far the most investigated aldehydic end-product of oxidative breakdown of membrane n-6 polyunsaturated fatty acids. Its potential involvement in the pathogenesis of atherosclerosis has been corroborated by its consistent detection in both oxidized LDL and fibrotic plaque in humans. HNE has been shown to activate both macrophage and smooth muscle cells, i.e. the two key cell types in chronic inflammatory processes characterized by excessive fibrogenesis. By signalling to the nucleus, the aldehyde may up-regulate in these cells both expression and synthesis of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta1 (TGFbeta1). Oxysterols, namely 27 carbon atoms oxidation products of cholesterol, are found in relatively high amount in LDL from hypercholesterolemic individuals and are consistently detectable in foam cells and necrotic core of human atherosclerotic lesion. As for HNE, the challenge of cells of the macrophage lineage with a mixture of oxysterols like that detectable in hypercholesterolemic individuals led to a marked overexpression of TGFbeta1 and MCP-1. Both HNE and oxysterols then appear to be candidates for a primary role in the progression of the atherosclerotic process.
 ...
PMID:4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. 1627 Feb 77

The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimer's disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
 ...
PMID:Calpain inhibition: a therapeutic strategy targeting multiple disease states. 1647 52

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.
 ...
PMID:Acrolein generation stimulates hypercontraction in isolated human blood vessels. 1709 30

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.
 ...
PMID:P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. 1719 91


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