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)

Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins and their receptors are heavily glycosylated and sialylated, and levels of sialic acids modulate their biological functions. Sialylation is controlled by the activities of sialyltranferases and sialidases. To address the impact of sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with a hypomorphic neu1 allele (B6.SM) that displays reduced sialidase expression and sialidase activity. The objectives of this study are to determine the impact of sialidase on the rate of hepatic lipoprotein secretion and lipoprotein uptake. Our results indicate that hepatic levels of cholesterol and triglycerides are significantly higher in B6.SM mice compared with C57Bl/6 mice; however, VLDL-triglyceride production rate is lower. In addition, B6.SM mice show significantly lower levels of hepatic microsomal triglyceride transfer protein (MTP) and active sterol-regulatory element binding protein (SREBP)-2 but higher levels of diglyceride acyltransferase (DGAT)2; these are all indicative of increased hepatic lipid storage. Rescue of sialidase activity in hypomorphic sialidase mice using helper-dependent adenovirus resulted in increased VLDL production and an increase in MTP levels. Furthermore, hypomorphic sialidase expression results in stabilization of hepatic LDL receptor (LDLR) protein expression, which enhances LDL uptake. These findings provide novel evidence for a central role of sialidase in the cross talk between the uptake and production of lipoproteins.
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PMID:Hypomorphic sialidase expression decreases serum cholesterol by downregulation of VLDL production in mice. 2298 45

Atherosclerosis is a complex disease that involves alterations in lipoprotein metabolism and inflammation. Protein and lipid glycosylation events, such as sialylation, contribute to the development of atherosclerosis and are regulated by specific glycosidases, including sialidases. To evaluate the effect of the sialidase neuraminidase 1 (NEU1) on atherogenesis, here we generated apolipoprotein E (ApoE)-deficient mice that express hypomorphic levels of NEU1 (Neu1hypoApoe-/-). We found that the hypomorphic NEU1 expression in male Apoe-/- mice reduces serum levels of very-low-density lipoprotein (VLDL) and LDL cholesterol, diminishes infiltration of inflammatory cells into lesions, and decreases aortic sinus atherosclerosis. Transplantation of Apoe-/- bone marrow (BM) into Neu1hypoApoe-/- mice significantly increased atherosclerotic lesion development and had no effect on serum lipoprotein levels. Moreover, Neu1hypoApoe-/- mice exhibited a reduction in circulating monocyte and neutrophil levels and had reduced hyaluronic acid and P-selectin adhesion capability on monocytes/neutrophils and T cells. Consistent with these findings, administration of a sialidase inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, had a significant anti-atherogenic effect in the Apoe-/- mice. In summary, the reduction in NEU1 expression or function decreases atherosclerosis in mice via its significant effects on lipid metabolism and inflammatory processes. We conclude that NEU1 may represent a promising target for managing atherosclerosis.
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PMID:Sialidase down-regulation reduces non-HDL cholesterol, inhibits leukocyte transmigration, and attenuates atherosclerosis in ApoE knockout mice. 3009 18

Sialic acid residues that make part of the cell surface repertoire of carbohydrate residues are implicated in various physiological processes and human pathologies. Sialidases, or neuraminidases, are the enzymes that are able to cleave and release the sialic acid residues, while trans-sialidases can transfer the residues from donor to acceptor molecules. They are important for processing the surface glycolipids and glycoproteins. Therapeutic potential of pharmacological sialidases inhibition is currently actively studied. Knowledge and expertise gained from genetic defects leading to human sialidase deficiency can be used for designing such drugs. In this review, we discuss the current progress in studying sialidases and their inhibitors and the relevance of these studies to developing novel therapeutic approaches. In vitro studies suggest that some sialidase inhibitors might be useful therapeutics for treating sialidosis, cancer, infections, immune diseases, atherosclerosis and other pathologies. Consequently, there is a field for further research and development. A thorough investigation of human sialidases is therefore crucial to human health.
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PMID:Diagnostics and Therapy of Human Diseases - Focus on Sialidases. 3019 28

Atherosclerosis is associated with the increased trans-sialidase activity, which can be detected in the blood plasma of atherosclerosis patients. The likely involvement in the disease pathogenesis made this activity an interesting research subject and the enzyme that may perform such activity was isolated and characterized in terms of substrate specificity and enzymatic properties. It was found that the enzyme has distinct optimum pH values, and its activity was enhanced by the presence of Ca2+ ions. Most importantly, the enzyme was able to cause atherogenic modification of lowdensity lipoprotein (LDL) particles in vitro. However, the identity of the discovered enzyme remained to be defined. Currently, sialyltransferases, mainly ST6Gal I, are regarded as major contributors to sialic acid metabolism in human blood. In this mini-review, we discuss the possibility that atherosclerosis- associated trans-sialidase does, in fact, belong to the sialyltransferases family.
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PMID:Trans-sialidase Associated with Atherosclerosis: Defining the Identity of a Key Enzyme Involved in the Pathology. 3084

Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.
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PMID:The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis. 3133 Aug 45

Sialic acid (Sia), the acylated derivative of the nine-carbon sugar neuraminic acid, is a terminal component of the oligosaccharide chains of many glycoproteins and glycolipids. In light of its important biological and pathological functions, the relationship between Sia and coronary artery disease (CAD) has been drawing great attentions recently. Large-scale epidemiological surveys have uncovered a positive correlation between plasma total Sia and CAD risk. Further research demonstrated that N-Acetyl-Neuraminic Acid, acting as a signaling molecule, triggered myocardial injury via activation of Rho/ROCK-JNK/ERK signaling pathway both in vitro and in vivo. Moreover, there were some evidences showing that the aberrant sialylation of low-density lipoprotein, low-density lipoprotein receptor and blood cells was involved in the pathological process of atherosclerosis. Significantly, the Sia regulates immune response by binding to sialic acid-binding immunoglobulin-like lectin (Siglecs). The Sia-Siglecs axis is involved in the immune inflammation of atherosclerosis. The generation of Sia and sialylation of glycoconjugate both depend on many enzymes, such as sialidase, sialyltransferase and trans-sialidase. Abnormal activation or level of these enzymes associated with atherosclerosis, and inhibitors of them might be new CAD treatments. In this review, we focus on summarizing current understanding of Sia metabolism and of its relevance to atherosclerosis.
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PMID:Sialic acid metabolism as a potential therapeutic target of atherosclerosis. 3152 Nov 72

Desialylation-loss of terminal sialic acid residues from glycoconjugates catalyzed by sialidases-is involved in many human diseases and is considered a key molecular event of atherosclerosis onset. Desialylated low-density lipoproteins with atherogenic properties have been detected in human blood previously. However, there is currently no consensus on the origin of desialylation activity in the bloodstream. Here, we suggest viral intervention as a possible explanation. In order to address our hypothesis, we studied seasonal patterns of blood serum sialidase enzymatic activity and designed an approach to detect and quantify viral sialidase genetic presence. Increased sialidase activity in autumn-winter combined with detectable levels of influenza virus sialidase mRNA suggests exogenous viral sialidase as a viable component of desialylation in human blood, providing new insights on the molecular background of atherogenesis.
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PMID:Sialidase Activity in Human Blood Serum Has a Distinct Seasonal Pattern: A Pilot Study. 3270 35

The most typical feature of atherogenesis in humans at its early stage is the formation of foam cells in subendothelial arterial intima, which occurs as the consequence of intracellular cholesterol deposition. The main source of lipids accumulating in the arterial wall are circulating low-density lipoprotein (LDL). However, LDL particles should undergo proatherogenic modification to acquire atherogenic properties. One of the known types of atherogenic modification of LDL is enzymatic deglycosilation, namely, desialylation, which is the earliest change in the cascade of following multiple LDL modifications. The accumulating data make sialidases an intriguing and plausible therapeutic target, since pharmacological modulation of activity of these enzymes may have beneficial effects in several pathologies, including atherosclerosis. The hypothesis exists that decreasing LDL enzymatic desialylation may result in prevention of lipid accumulation in arterial wall, thus breaking down one of the key players in atherogenesis at the cellular level. Several drugs acting as glycomimetics and inhibiting sialidase enzymatic activity already exist, but the concept of sialidase inhibition as an anti-atherosclerosis strategy remains unexplored to date. This review is focused on the potential possibilities of the repurposing of sialidase inhibitors for pathogenetic anti-atherosclerotic therapy.
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PMID:Prospects for the Use of Sialidase Inhibitors in Anti-atherosclerotic Therapy. 3286 33


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