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 enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02-29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.
 ...
PMID:Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease. 1592 79

Excessive or misplaced activation of leukocytes causes host tissue damage which has been implicated in diseases such as atherosclerosis and chronic inflammation. This may arise via either the generation of oxidants such as hypochlorous acid (HOCl) by the heme enzyme myeloperoxidase, the action of released enzymes including lysozyme and proteases, or a combination of these two activities. Thus, oxidant-mediated inactivation of protease inhibitors that modulate tissue proteolysis by the released enzymes may exacerbate protease-induced degradation of host tissue. The role of myeloperoxidase-derived oxidants, such as HOCl, in the inactivation of Kunitz-type inhibitors and lysozyme is not well-characterized and is the subject of the current study. Exposure of both trypsin inhibitor and lysozyme to low molar excesses of HOCl compared to protein is shown to result in loss of function. With trypsin inhibitor, this loss of activity is associated with the selective oxidation of Trp, Tyr, and His residues, which results in protein unfolding and the disruption of complex formation with active trypsin. Oxidation of Met residues, a major target for HOCl, or the active site Arg, does not appear to play a key role in this loss of activity. In contrast, with lysozyme, oxidation of Met residues to Met sulfoxide appears to be the major process resulting in loss of enzyme activity. With both proteins, inactivation occurs in a time-dependent manner, consistent with both direct oxidation by HOCl and secondary reactions of protein chloramines formed from amine groups (e.g., from Lys and His) playing a role in loss of activity.
 ...
PMID:Inactivation of protease inhibitors and lysozyme by hypochlorous acid: role of side-chain oxidation and protein unfolding in loss of biological function. 1653 25

The heme enzyme myeloperoxidase (MPO) is released at sites of inflammation by activated leukocytes. A key function of MPO is the production of hypohalous acids (HOX, X = Cl, Br) which are strong oxidants with potent antibacterial properties. However, HOX can also damage host tissue when produced at the wrong place, time or concentration; this has been implicated in several human diseases. Thus, elevated blood and leukocyte levels of MPO are significant independent risk factors for atherosclerosis, and specific markers of HOX-mediated protein oxidation are often present at elevated levels in patients with inflammatory diseases (e.g. asthma). HOX react readily with amino acids, proteins, carbohydrates, lipids, nucleobases and antioxidants. Sulfur-containing amino acids (Cys, Met, cystine) and amines on amino acids, nucleobases, sugars and lipids are the major targets for HOX. Reaction with amines generates chloramines (RNHCl) and bromamines (RNHBr), which are more selective oxidants than HOX and are key intermediates in HOX biochemistry. As these and other products of MPO-derived oxidants are unstable, understanding the role of HOX-induced damage in disease cannot be obtained solely by stable product analysis, and knowledge of the reaction kinetics is essential. This review collates kinetic and product data for HOX, chloramine and bromamine reactions with biological substrates. It highlights how kinetic data may be used to predict the effect of HOX-mediated oxidation on complex biological targets, such as lipoproteins and extracellular matrix in atherosclerosis, or protein-DNA complexes in cancer, thereby providing a basis for unraveling the mechanisms by which these oxidants generate biological damage.
 ...
PMID:Reactions of myeloperoxidase-derived oxidants with biological substrates: gaining chemical insight into human inflammatory diseases. 1716 51

Modification of biomolecules by reactive aldehydes is believed to play a role in biological processes, including aging, atherosclerosis, and Alzheimer's disease. Here, the modification of cytochrome c promoted by trans, trans-2,4-decadienal (DDE) was investigated. Matrix-assisted laser desorption/ionization time-of-flight experiments indicated increases in the molecular weight of cytochrome c, consistent with the formation of DDE adducts. Our data show that the protein modification was time-, pH-, and DDE concentration-dependent, leading to the formation of at least six adducts after 2 h of incubation at pH 7.4. Electrospray ionization quantitative TOF mass spectrometry analysis of tryptic digests indicated that His-33, Lys-39, Lys-72, and Lys-100 were modified by DDE. These adducts could have significant effects considering that His-33, Lys-72, and Lys-100 are present in clusters of basic amino acid residues, which are believed to participate in the interaction of cytochrome c with cardiolipin in the inner mitochondrial membrane and cytochrome c oxidase. A blue shift in the cytochrome c Soret band from 409 to 406 nm was also observed after DDE reaction, indicating heme crevice opening and displacement of heme sixth ligand (Met-80) coordination in modified protein. The covalent modifications in cytochrome c could play a role in mitochondrial dysfunction associated with oxidative stress.
 ...
PMID:Covalent modification of cytochrome c exposed to trans,trans-2,4-decadienal. 1765 62

Atherosclerosis is the underlying pathological process of most cardiovascular disease. A critical component of the "response to retention" hypothesis of atherogenesis is proteoglycan/low density lipoprotein (LDL) binding. Transforming growth factor beta (TGF-beta) is present in atherosclerotic lesions, regulates vascular smooth muscle cell (VSMC) proteoglycan synthesis via an unknown signaling pathway, and increases proteoglycan/LDL binding. This pathway was investigated using the activin receptor-like kinase 5 (ALK5) inhibitor SB431542 and inhibitors of p38 MAP kinase as a possible downstream or alternative mediator. TGF-beta stimulated and SB431542 inhibited the phosphorylation of Smad2/3. In human VSMC, TGF-beta increased [(35)S]sulfate incorporation into proteoglycans associated with a 19% increase in glycosaminoglycan (GAG) chain size by size exclusion chromatography. SB431542 caused a concentration-dependent decrease in TGF-beta-mediated [(35)S]sulfate incorporation with 92% inhibition at 3 mum. Two different p38 MAP kinase inhibitors, SB203580 and SB202190, but not the inactive analogue SB202474, concentration-dependently blocked TGF-beta-mediated [(35)S]sulfate incorporation. TGF-beta increased [(3)H]glucosamine incorporation into glycosaminoglycans by 180% and [(35)S]Met/Cys incorporation into proteoglycan core proteins by 35% with both effects completely inhibited by SB431542. Blocking both Smad2/3 and p38 MAP kinase pathways prevented the effect of TGF-beta to increase proteoglycan to LDL binding. TGF-beta mediates its effects on proteoglycan synthesis in VSMCs via the ALK5/Smad2/3 phosphorylation pathway as well as via the p38 MAP kinase signaling cascade. Further studies of downstream pathways controlling proteoglycan synthesis may identify potential therapeutic targets for the prevention of atherosclerosis and cardiovascular disease.
 ...
PMID:Smad and p38 MAP kinase-mediated signaling of proteoglycan synthesis in vascular smooth muscle. 1822 58

High-density lipoproteins (HDLs) prevent atherosclerosis by removing cholesterol from macrophages and by providing antioxidants for low-density lipoproteins. Oxidation of HDLs affects their functions via the complex mechanisms that involve multiple protein and lipid modifications. To differentiate between the roles of oxidative modifications in HDL proteins and lipids, we analyzed the effects of selective protein oxidation by hypochlorite (HOCl) on the structure, stability, and remodeling of discoidal HDLs reconstituted from human apolipoproteins (A-I, A-II, or C-I) and phosphatidylcholines. Gel electrophoresis and electron microscopy revealed that, at ambient temperatures, protein oxidation in discoidal complexes promotes their remodeling into larger and smaller particles. Thermal denaturation monitored by far-UV circular dichroism and light scattering in melting and kinetic experiments shows that protein oxidation destabilizes discoidal lipoproteins and accelerates protein unfolding, dissociation, and lipoprotein fusion. This is likely due to the reduced affinity of the protein for lipid resulting from oxidation of Met and aromatic residues in the lipid-binding faces of amphipathic alpha-helices and to apolipoprotein cross-linking into dimers and trimers on the particle surface. We conclude that protein oxidation destabilizes HDL disk assembly and accelerates its remodeling and fusion. This result, which is not limited to model discoidal but also extends to plasma spherical HDL, helps explain the complex effects of oxidation on plasma lipoproteins.
 ...
PMID:Effects of protein oxidation on the structure and stability of model discoidal high-density lipoproteins. 1830 37

4-Hydroxynonenal (HNE) is known to be atherogenic, but its mechanism of action in atherogenesis is not clear. Therefore, this study investigated the role of HNE in macrophage foam cell formation and the underlying mechanism involved in HNE-induced expression of scavenger receptors (SRs). In the aortic sinus of ApoE-deficient mice fed a high-fat diet, multiple plaque lesions were accompanied by increased accumulation of HNE adducts in the enhanced Mac-2 stained area. In an in vitro study, HNE exposure to J774A.1 macrophages led to increased expression of class A SR (SR-A) and CD36 at the protein level with a concomitant increase in endocytic uptake of oxLDL. In contrast to CD36 protein expression, which was associated with an increase in mRNA expression, the HNE-enhanced SR-A protein expression was neither accompanied by its mRNA expression nor affected by actinomycin D. HNE enhanced the incorporation rates of (35)S-Met/Cys into SR-A, and HNE-induced SR-A protein expression was effectively attenuated by translation inhibitors such as cycloheximide and rapamycin. Taken together, these data suggest that HNE contributes to macrophage foam cell formation through increased synthesis of SR-A at the level of mRNA translation, consequently leading to the progression of atherosclerosis.
 ...
PMID:4-hydroxynonenal contributes to macrophage foam cell formation through increased expression of class A scavenger receptor at the level of translation. 1845 3

Atherosclerosis is a multifactorial disease caused by the interaction between genetic predisposition and environmental influences. Polymorphisms within platelet membrane antigens have been recognized as a potential risk factor involved in pathogenesis of coronary artery disease (CAD). Results of different studies on association of platelet membrane polymorphisms and CAD are controversial. The aim of our study was to investigate the frequency of GPIbalpha145Thr/Met (HPA-2) polymorphism among Croatian patients and to assess the relationship between this polymorphism and the prevalence of CAD. 604 patients were enrolled in this investigation and according to the results of coronary angiograms were devided in two groups: 402 patients with coronary angiography confirmed CAD and 202 patients without coronary angiography confirmed CAD (control group). Frequency of genotypes HPA-2ab (Thr/Met) and HPA-2bb (Met/Met) was higher in CAD group than in control group (22.1% vs 21.3% and 1.3% vs 0,5%) but the difference was not statistically significant (p = 0.654). Among CAD patients, the frequency of Met allele was nonsignificantly higher than among control group patients (0.12 vs 0.11). Statistical analysis showed no significant connection between GPIbalpha145Thr/Met (HPA-2) polymorphism and CAD (OR, 1.10; 95% CI, 0.69 do 1.50). This is in concordance with the results of investigation conducted among central Europeans. The relationship of other platelet glycoprotein polymorphisms and CAD among Croatians remains to be investigated.
 ...
PMID:[Polymorphism of platelet glycoprotein Ibalpha as a genetic predictor of coronary artery disease]. 1879 63

Monocytes/macrophages recruited into the arterial wall during atherogenesis are crucial in the initiation and progression of atherosclerosis and play a fundamental role in the destabilization process that is the main causal event of acute coronary syndromes. In the present study, we investigated the effect of the mammalian target of rapamycin inhibitor everolimus on macrophage accumulation within carotid lesions elicited by perivascular collar placement in cholesterol-fed rabbits. Everolimus (1.5 mg/kg given 1 day before collaring followed by 1 mg/kg/day for 14 days, administered by oral gavage) markedly decreased lesion macrophage content as compared with vehicle control (-65%; p < 0.01). This effect was associated with a reduction in intimal thickening and occurred in the absence of changes in plasma cholesterol concentrations. To gain insights on the potential mechanism(s) underlying this effect, we investigated the influence of everolimus on chemoattractant-induced migration of human monocytes in vitro. Pretreatment with therapeutic concentrations of everolimus (10 nM) significantly lowered monocyte chemotaxis in response to various chemotactic factors (i.e., monocyte chemoattractant protein-1/CCL2, fractalkine/CX3CL1, interleukin-8/CXCL8, complement fragment 5a, or N-formyl-Met-Leu-Phe) without inducing monocyte cell death. These results suggest that everolimus may favorably influence the atherosclerotic process by affecting the recruitment of monocytes into early lesions.
 ...
PMID:Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. 1902 42

Atherosclerosis is associated with dysfunctional HDL, and oxidation of HDL is thought to give rise to HDL becoming dysfunctional. Lipoprotein oxidation represents a complex series of processes that can be assessed by various methods. In general, oxidation mediated by 1-electron or radical oxidants gives rise to lipid hydroperoxides (LOOHs) as the primary product. These LOOHs may then undergo further reactions giving rise to secondary lipid oxidation products and/or oxidation of lipoprotein-associated proteins. Thus, LOOHs specifically oxidize Met residues of apolipoprotein (apo) A-I and A-II (the major proteins of HDL) to MetO. Here we describe an HPLC-based method to detect oxidized HDL containing specifically oxidized forms of apoA-I and apoA-II. This method may be useful to assess the early stages of HDL oxidation in biological samples.
 ...
PMID:Detection of specifically oxidized apolipoproteins in oxidized HDL. 1908 38


<< Previous 1 2 3 4 5 6 7 Next >>