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

The importance of apolipoprotein A-I (apoA-I) in atherosclerosis was established by testing in animal models, and its potential usefulness in humans has been confirmed in preliminary studies. ApoA-I is a large protein comprising 243 amino acids, which means that venous administration is necessary. In addition, manufacture of apoA-I is difficult and expensive. Research has, therefore, been directed towards finding smaller peptide mimetics that produce similar results to apoA-I, but that are easier to manufacture and administer. The earliest peptides mimicked some of the lipid-binding properties of apoA-I but did not prevent atherosclerosis in mice. A detailed study of the physical-chemical characteristics of these peptides led to the realization that the hydrophobic region of the peptide was critical in determining bioactivity. A potent peptide, 4F, which was synthesized wholly from D-amino acids, could be given orally. Use of 4F significantly improved the function of HDL in mice and monkeys. When 4F was administered in combination with a statin, lesion size and macrophage content were reduced in mice with atherosclerosis, and lesions regressed in older mice. Vasoreactivity and endothelial sloughing were also improved in other rodent studies. Early human clinical trials are now being carried out on 4F. Here, we review the studies on apoA-I mimetic peptides that have been carried out so far.
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PMID:Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention. 1699 Aug 39

It is well accepted that high levels of high density lipoproteins (HDL) reduce the risk of atherosclerosis in humans. Apolipoprotein A-I (apoA-I) and apoA-II are the first and second most common protein constituents of HDL. Unlike apoA-I, detailed structural models for apoA-II in HDL are not available. Here, we present a structural model of apoA-II in reconstituted HDL (rHDL) based on two well established experimental approaches: chemical cross-linking/mass spectrometry (MS) and internal reflection infrared spectroscopy. Homogeneous apoA-II rHDL were reacted with a cross-linking agent to link proximal lysine residues. Upon tryptic digestion, cross-linked peptides were identified by electrospray mass spectrometry. 14 cross-links were identified and confirmed by tandem mass spectrometry (MS/MS). Infrared spectroscopy indicated a beltlike molecular arrangement for apoA-II in which the protein helices wrap around the lipid bilayer rHDL disc. The cross-links were then evaluated on three potential belt arrangements. The data clearly refute a parallel model but support two antiparallel models, especially a "double hairpin" form. These models form the basis for understanding apoA-II structure in more complex HDL particles.
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PMID:The structure of apolipoprotein A-II in discoidal high density lipoproteins. 1726 82

Apolipoprotein A-I (apoA-I), the major protein constituent within high-density lipoprotein (HDL), has been associated with antiatherogenic protection by mechanisms that include reverse cholesterol transport and antiinflammatory functions. To evaluate the proposed protective function of apoA-I, proteins modified by nitrating oxidants were evaluated in the aortic tissue and plasma of mice lacking the low-density lipoprotein receptor and apobec (LA) and LA mice with genetic deletion of apoA-I (LA-apoA-I(-/-)). The levels of nitrated proteins in aortic tissue quantified by liquid chromatography with online electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) were 6-fold higher in the LA-apoA-I(-/-) as compared with the LA mice. The quantitative analyses were corroborated by immunohistochemical and high-resolution immunoelectron microscopic evaluation of the lesions, which revealed abundant staining for nitrated proteins in the aortic root lesions of LA-apoA-I(-/-) as compared with the LA mice. Proteomic approaches based on affinity enrichment and site-specific adduct mapping identified unique specific protein targets for nitration in the plasma of LA-apoA-I(-/-) that were not present in the plasma of LA mice. In particular the nitration of fibrinogen was shown to accelerate fibrin clot formation. Another consequence of the augmented levels of nitrated proteins was the induction of humoral responses documented by the increased circulating immunoglobulins that recognize nitrotyrosine in LA-apoA-I(-/-) as compared with the LA mice. These data collectively support a protective function of apoA-I diminishing the burden of nitrative oxidants in these mice models of atherosclerosis.
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PMID:Increased protein nitration burden in the atherosclerotic lesions and plasma of apolipoprotein A-I deficient mice. 1761 69

Irreversible myocardial injury is a potential consequence of coronary artery revascularization. Reperfusion leads to the production of oxidized products that can damage myocardium. High-density lipoproteins (HDL) are effective at removing oxidized lipids. We hypothesized that a synthetic HDL preparation, comprising recombinant apolipoprotein A-I(Milano) (apoA-I(M)) complexed with 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) (apoA-I(M)/POPC) would protect the heart from reperfusion injury. The ex vivo model consisted of rabbit hearts perfused by the Langendorff method. Hearts were equilibrated with Krebs-Henseleit buffer (10 min), pretreated with either apoA-I(M)/POPC (0.45 mg/mL) or vehicle (10 min), subjected to global ischemia (30 min) and reperfused for 60 min. ApoA-I(M)/POPC (n=7) prevented the left ventricular end-diastolic pressure elevation observed in the vehicle group (n=6) at the end of reperfusion (p<0.05). During reperfusion, coronary artery perfusion pressure increased in the controls (p<0.001), but not with apoA-I(M)/POPC. ApoA-I(M)/POPC reduced the release of creatine kinase at the end of the ischemic period (p<0.001). It also reduced cardiac left ventricle muscle lipid hydroperoxides by 46% (p<0.05). Direct comparison of the antioxidant potential indicated that recombinant apoA-I(M) was much more potent than apoA-I in attenuating low-density lipoprotein oxidation. Electron microscopy showed that apoA-I(M)/POPC prevented mitochondrial granulation, disorganization and sarcomere contraction band formation indicative of reperfusion injury. The apoA-I(M)/POPC complex thus appears to reduce reperfusion injury under global ischemic conditions, and may therefore have therapeutic application in the reduction of myocardial ischemia.
Atherosclerosis 2008 Apr
PMID:Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart. 1794 38

High-density lipoproteins (HDLs) are complexes of proteins (mainly apoA-I and apoA-II) and lipids that remove cholesterol and prevent atherosclerosis. Understanding the distinct properties of the heterogeneous HDL population may aid the development of new diagnostic tools and therapies for atherosclerosis. Mature human HDLs form two major subclasses differing in particle diameter and metabolic properties, HDL(2) (large) and HDL(3) (small). These subclasses are comprised of HDL(A-I) containing only apoA-I, and HDL(A-I/A-II) containing apoA-I and apoA-II. ApoA-I is strongly cardioprotective, but the function of the smaller, more hydrophobic apoA-II is unclear. ApoA-II is thought to counteract the cardioprotective action of apoA-I by stabilizing HDL particles and inhibiting their remodeling. To test this notion, we performed the first kinetic stability study of human HDL subclasses. The results revealed that the stability of plasma spherical HDL decreases with increasing particle diameter; which may facilitate preferential cholesterol ester uptake from large lipid-loaded HDL(2). Surprisingly, size-matched plasma HDL(A-I/A-II) showed comparable or slightly lower stability than HDL(A-I); this is consistent with the destabilization of model discoidal HDL observed upon increasing the A-II to A-I ratio. These results clarify the roles of the particle size and protein composition in HDL remodeling, and help reconcile conflicting reports regarding the role of apoA-II in this remodeling.
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PMID:Differential stability of high-density lipoprotein subclasses: effects of particle size and protein composition. 1923 80

Lecithin-cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism, has been proposed to have atheroprotective properties by promoting reverse cholesterol transport. Overexpression of LCAT in various animal models, however, has led to conflicting results on its overall effect on lipoproteins and atherosclerosis. In this study, the effect of overexpression of LCAT in nonhuman primates on lipoprotein metabolism is examined. Human LCAT was expressed with adenovirus in squirrel monkeys (n = 8), resulting on day 4 in a 22-fold increase of LCAT activity (257 +/- 23 vs 5618 +/- 799 nmol mL(-1) h(-1), P < .0001). At its peak, LCAT was found to nearly double the level of HDL cholesterol from baseline (113 +/- 7 vs 260 +/- 24 mg/dL, P < .01). High-density lipoprotein formed after treatment with the adenovirus was larger in size, as assessed by fast protein liquid chromatography (FPLC) analysis. By kinetic studies, it was determined that there was a decrease in apolipoprotein (Apo) A-I resident time (0.373 +/- 0.027 vs 0.685 +/- 0.045 d(-1), P < .0001) and almost a doubling in the ApoA-I synthetic rate (22 +/- 2 vs 41 +/- 3 mg kg(-1) d(-1), P < .0001), but no overall change in ApoA-I levels. In addition, increased expression of LCAT was associated with a 37% reduction of ApoB levels (12 +/- 1 vs 19 +/- 1 mg/dL, P < .05) due to increased low-density lipoprotein catabolism (fractional catabolic rate = 1.7 +/- 0.1 d(-1) in controls vs 4.2 +/- 0.3 d(-1) in LCAT-treated group, P < .05). In summary, overexpression of LCAT in nonhuman primates leads to an antiatherogenic lipoprotein profile by increasing HDL cholesterol and lowering ApoB, thus making LCAT a potential drug target for reducing atherosclerosis.
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PMID:Adenoviral expression of human lecithin-cholesterol acyltransferase in nonhuman primates leads to an antiatherogenic lipoprotein phenotype by increasing high-density lipoprotein and lowering low-density lipoprotein. 1930 80

C-reactive protein (CRP) is an acute phase protein and a biochemical marker with important prognostic value for cardiovascular events. Interleukins IL-1 and IL-6 are implicated in the pathogenesis of atherosclerosis and are associated with CRP. Apolipoproteins ApoA-I and ApoB are the main lipid metabolic markers implicated in the development and progression of atherosclerosis. Fibrinogen has also been proposed to be a major independent risk factor for cardiovascular events. Because premature atherosclerosis precedes the development of cardiovascular disease, identification of the associated biomarkers is of great importance. However, further studies will be needed to determine whether or not these markers are useful predictors of future cardiovascular events. Here, we review the roles of specific biomarkers that have been implicated in premature atherosclerosis.
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PMID:Biomarkers of premature atherosclerosis. 1957 61

High levels of high-density lipoprotein (HDL) have protective effects against atherosclerosis and cardiovascular diseases. The postulated mechanism of action for these benefits is an enhanced reverse cholesterol transport. Apolipoprotein A-I (ApoA-I) is the major protein of HDL. The clinical benefits of raising ApoA-I/HDL have been clearly established by clinical and epidemiological studies. Despite these observations, there are not very effective pharmacological means for raising HDL. ApoA-I gene delivery by viral vectors seems a promising strategy to raise ApoA-I/HDL levels. Sustained gene expression in animals and humans has been attained using adeno-associated viral (AAV) vectors. The aim of the present study was to determine the efficiency, safety, and biological activity of human ApoA-I intramuscularly delivered using an AAV vector in mice. AAV serotype 8 vectors encoding for human ApoA-I transgene were administered intraportally and intramuscularly in ApoA-I- deficient animals. ApoA-I levels were measured every 2 weeks post administration. The effectiveness of the generated HDL was tested in vitro in cholesterol-loaded macrophages. The administration of the vectors resulted in a significant and sustained increase in ApoA-I and HDL plasma levels for up to 16 weeks at similar extent by both routes of administration. Activity of the generated HDL in removal of cholesterol from cholesterol-loaded macrophages was similar in both groups. Our data suggest that intramuscular AAV8-mediated gene transfer of human ApoA-I results in a significant and maintained increase in ApoA-I and functional HDL.
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PMID:Safe and sustained overexpression of functional apolipoprotein A-I/high-density lipoprotein in apolipoprotein A-I-null mice by muscular adeno-associated viral serotype 8 vector gene transfer. 1970 Oct 94

Apolipoprotein A-I (apoA-I) mimetic peptides have been pursued as new therapeutic agents for the treatment of atherosclerosis, yet their precise mechanism responsible for atheroprotection remains unclear. Like apoA-I itself, most of these peptides are capable of stimulating cholesterol efflux from macrophages or foam cells, and some of them stimulate lecithin cholesterol acyltransferase (LCAT) activity in the reverse cholesterol transport (RCT) pathway. However, the ability of mimetic peptides to deliver cholesterol into hepatocytes (off-loading), the last step of the RCT pathway, has not been demonstrated. In this study, we compared a mimetic peptide D-4F to purified apoA-I, to address the role that mimetics play during the off-loading process. Both D-4F and apoA-I formed spherical nano-particles when reconstituted with cholesteryl ester and phospholipids. Compared to apoA-I, D-4F particles were 20 times more efficient in off-loading cholesterol to HepG2 hepatocytes with an apparent K(t) (transport) of 0.74 mug/mL. Furthermore, D-4F also facilitated cholesteryl ester offloading from HDL particles into HepG2 cells when it was pre-incubated with these HDL particles. Using an inducible HEK293 cell line, we demonstrated that these nano-particles were able to be taken up through SR-BI, a HDL selective receptor. Cholesterol uptake by HepG2 cells was completely blocked by a neutralizing monoclonal antibody against SR-BI, demonstrating that D-4F particles, similar to HDL, specifically off-loaded cholesterol through SR-BI. Overall our data provides evidence that D-4F is capable of mimicking apoA-I to form HDL-like particles, and off-loads cholesterol for catabolism and excretion, thus completing RCT.
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PMID:An apoA-I mimetic peptide facilitates off-loading cholesterol from HDL to liver cells through scavenger receptor BI. 1984 20

Non-enzymatic glycation of serum apolipoproteins is a main feature of diabetes mellitus under hyperglycemia. Advanced glycation end products are implicated in the development of aging and metabolic syndrome, including premature atherosclerosis in diabetic subjects. ApoA-I is the principal protein constituent of HDL. In this study, glycated human apoA-I (gA-I) by fructation was characterized on functional and structural correlations in lipid-free and lipid-bound states. The gA-I showed more spontaneous multimeric band formation up to pentamer and exhibited slower elution profile with more degraded fragments from fast protein liquid chromatography. The gA-I showed modified secondary structure from fluorescence and circular dichroism analysis. Reconstituted high-density lipoprotein (rHDL) containing the gA-I had less content of phospholipid with a much smaller particle size than those of rHDL-containing nA-I (nA-I-rHDL). The rHDL containing gA-I (gA-I-rHDL) consisted of less molecular number of apoA-I than nA-I-rHDL with decreased alpha-helical content. Treatment of the gA-I-rHDL induced more atherogenic process in macrophage cell and premature senescence in human dermal fibroblast cell. Conclusively, fructose-mediated apoA-I glycation resulted in severe loss of several beneficial functions of apoA-I and HDL regarding anti-senescence and anti-atherosclerosis activities due to a lack of anti-oxidant activity with increased susceptibility of protein degradation and structural modification.
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PMID:Fructated apolipoprotein A-I showed severe structural modification and loss of beneficial functions in lipid-free and lipid-bound state with acceleration of atherosclerosis and senescence. 2005 75


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