Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis.

In the modern world, cardiovascular diseases have a special place among the most common causes of death. Naturally, this widespread problem cannot escape the attention of scientists and researchers. One of the main conditions preceding the development of fatal cardiovascular diseases is atherosclerosis. Despite extensive research into its pathogenesis and possible prevention and treatment strategies, many gaps remain in our understanding of this disease. For example, the concept of multiple low-density lipoprotein modifications was recently stated, in which desialylation is of special importance. Apart from this, sialic acids are known to be important contributors to processes such as endothelial dysfunction and inflammation, which in turn are major components of atherogenesis. In this review, we have collected information on sialic acid metabolism, analyzed various aspects of its implication in atherosclerosis at different stages, and provided an overview of the role of particular groups of enzymes responsible for sialic acid metabolism in the context of atherosclerosis.

Sialic acid as the potential link between lipid metabolism and inflammation in the pathogenesis of atherosclerosis

In the modern world, cardiovascular diseases have a special place among the most common causes of death. Naturally, this widespread problem cannot escape the attention of scientists and researchers. One of the main conditions preceding the development of fatal cardiovascular diseases is atherosclerosis. Despite extensive research into its pathogenesis and possible prevention and treatment strategies, many gaps remain in our understanding of this disease. For example, the concept of multiple low-density lipoprotein modifications was recently stated, in which desialylation is of special importance. Apart from this, sialic acids are known to be important contributors to processes such as endothelial dysfunction and inflammation, which in turn are major components of atherogenesis. In this review, we have collected information on sialic acid metabolism, analyzed various aspects of its implication in atherosclerosis at different stages, and provided an overview of the role of particular groups of enzymes responsible for sialic acid metabolism in the context of atherosclerosis.

Molecular Pathogenesis and the Possible Role of Mitochondrial Heteroplasmy in Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is a life-threatening condition associated with high mortality, in which the aortic wall is deformed due to congenital or age-associated pathological changes. The mechanisms of TAA development remain to be studied in detail, and are the subject of active research. In this review, we describe the morphological changes of the aortic wall in TAA. We outline the genetic disorders associated with aortic enlargement and discuss the potential role of mitochondrial pathology, in particular mitochondrial DNA heteroplasmy, in the disease pathogenesis.

Diagnostics and Therapy of Human Diseases - Focus on Sialidases.

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.

Multiple-modified Low-Density Lipoprotein as Atherogenic Factor of Patients' Blood: Development of Therapeutic Approaches to Reduce Blood Atherogenicity.

Generally, atherosclerosis first occurs by the way of accumulation of intracellular and extracellular lipids in the arterial intima. Foam cells, overloaded by lipids, are the essential harbinger of the coronary artery disease. It should be noted that lipids that are usually composed of bulk of the intracellular lipids found in human arterial cells originate from low-density lipoprotein (LDL) circulating in human blood. Nonetheless, many efforts to force cells to accumulate cholesteryl esters under the influence of native LDL have been unsuccessful. Whilst LDL modified in vitro (exposed to malondialdehyde, oxidized with ions of transition metals, acetylated, etc.) promoted accumulation of lipids in cells, all the attempts made for the sake of hunting down such LDLs in the bloodstream still do not provide confident conclusions. Therefore, a controversy arose: firstly, lipids from the cells of vascular wall have proved to be descending from LDL; secondly, foam cells do not form under the influence of native LDL in vitro (i.e. no visible intracellular lipid deposition observed); thirdly, chemically manipulated LDL seems to possess atherogenic properties. Acetylated LDL was not found in the bloodstream; similarly, the existence of oxidized LDL in the circulation remains controversial. Such a conundrum sparked a thorough investigation, leading to some interesting results. Modified desialylated LDL in human blood stream has been identified, which was able to promote lipid deposition in cultured cells. Such an LDL has been isolated, displaying atherogenic properties. The atherogenic LDL seems to deviate in multiple features from its non-atherogenic counterparts: carbohydrate, protein, and lipid moieties which were mangled. Such multiple LDL transformations take place in human blood stream and seem to denote a succession of events forcing the particle to become atherogenic: desialylation, lipid loss, shrinkage, rising of surface electronegative charge, etc. On top of the fat deposition in cells, multiple modifications of LDL as well as some other deleterious effects, like cell proliferation and fibrosis, seem to be part of the chain of events finally unfolding into a full-scale atherosclerotic lesion.

[DESIALATED LOW DENSITY LIPOPROTEINS IN HUMAN BLOOD].

The present article is a review of literature on circulating low-density lipoproteins (LDLP) which can induce accumulation of lipids (mainly, cholesterol), in a SMA(+) cell culture of normal human aortic intima. An attempt was undertaken to resolve the paradox of the absence of both native LDLP influence on intracellular lipid accumulation and modifications of in vitro obtained LDLP in the blood-vascular system. It was showed that atherogenic LDLPs are characterized by a number of changes in carbon, protein and lipid components which can be regarded as multiple modifications of LDLP taking place in human blood plasma. Multiply modified circulating LDLP possess of capacity to interact with various cell membrane receptors differing from B and E receptor, and with proteoglycans. Marked absorption of desiliated LDLPs by the cells simultaneous with a decrease in the degradation of apolipoproteins and cholesterol esters as well as induction of peresterification of free cholesterol leads to intracellular accumulation of esterified cholesterol. Formation of large LDLP-containing complexes especially circulating low-density lipoproteins can stimulate accumulation of lipids by smooth muscle cells of intima. Desiliated LDLPs stimulated cell proliferation and connective tissue matrix synthesis despite cholesterol ester accumulation. In conclusion, the authors of this article found and characterized natural multiply modified LDLPs that can be responsible for the symptoms of atherosclerosis at the cellular level.

[Atherogenic modification of low-density lipoproteins]. / Aterogennye modifikatsii lipoproteinov nizkoi plotnosti.

One of the first manifestations of atherosclerosis is accumulation of extra- and intracellular cholesterol esters in the arterial intima. Formation of foam cells is considered as a trigger in the pathogenesis of atherosclerosis. Low density lipoprotein (LDL) circulating in human blood is the source of lipids accumulated in the arterial walls. This review considered features and role in atherogenesis different modified forms of LDL: oxidized, small dense, electronegative and especially desialylated LDL. Desialylated LDL of human blood plasma is capable to induce lipid accumulation in cultured cells and it is atherogenic. LDL possesses numerous alterations of protein, carbohydrate and lipid moieties and therefore can be termed multiple-modified LDL. Multiple modification of LDL occurs in human blood plasma and represents a cascade of successive changes in the lipoprotein particle: desialylation, loss of lipids, reduction in the particle size, increase of surface electronegative charge, etc. In addition to intracellular lipid accumulation, stimulatory effects of naturally occurring multiple-modified LDL on other processes involved in the development of atherosclerotic lesions, namely cell proliferation and fibrosis, were shown.

Lipid composition of circulating multiple-modified low density lipoprotein.

Atherogenic modified low- density lipoprotein (LDL) induces pronounced accumulation of cholesterol and lipids in the arterial wall, while native LDL seems to lack such capability. Therefore, modified LDL appears to be a major causative agent in the pathogenesis of atherosclerosis. Possible modifications of LDL particles include changes in size and density, desialylation, oxidation and acquisition of negative charge. Total LDL isolated from pooled plasma of patients with coronary atherosclerosis, as well as from healthy subjects contains two distinct subfractions: normally sialylated LDL and desialylated LDL, which can be isolated by binding to a lectin affinity column. We called the desialylated LDL subfraction circulating modified LDL (cmLDL). In this study, we focused on lipid composition of LDL particles, analysing the total LDL preparation and two LDL subfractions: cmLDL and native LDL. The composition of LDL was studied using thin-layer chromatography. We found that cmLDL subfraction had decreased levels of free and esterified cholesterol, triglycerides, phospholipids (except for lysophosphatidylcholine) and sphingomyelin in comparison to native LDL. On the other hand, levels of mono-, and diglycerides, lysophosphatidylcholine and free fatty acids were higher in cmLDL than in native LDL. Our study demonstrated that lipid composition of cmLDL from atherosclerotic patients was altered in comparison to healthy subjects. In particular, phospholipid content was decreased, and free fatty acids levels were increased in cmLDL. This strengthens the hypothesis of multiple modification of LDL particles in the bloodstream and underscores the clinical importance of desialylated LDL as a possible marker of atherosclerosis progression.

[Epigenetic factors in atherogenesis: microRNA].

MicroRNAs (miRNAs) are small (~22 nucleotides in length) noncoding RNA sequences regulating gene expression at posttranscriptional level. MicroRNAs bind complementarily to certain mRNA and cause gene silencing. The involvement of miRNAs in the regulation of lipid metabolism, inflammatory response, cell cycle progression and proliferation, oxidative stress, platelet activation, endothelial and vascular smooth muscle cells (VSMC) function, angiogenesis and plaque formation and rapture indicates important roles in the initiation and progression of atherosclerosis. The key role of microRNAs in pathophysiology of cardiovascular diseases (CVDs), including atherosclerosis, was demonstrated in recent studies. Creating antisense oligonucleotides is a novel technique for selective changes in gene expression both in vitro and in vivo. In this review, we draw attention to the role of miRNAs in atherosclerosis progression, using miRNA as the potential biomarkers and targets in the CVDs, as well as possible application of antisense oligonucleotides.

[Modern methods of diagnosis dyslipidemia ].

Dyslipidemia is abnormalities of lipid and lipoprotein metabolism. Most dyslipidemias are hyperlipidemias; that is an abnormally high level of lipids and/or lipoproteins in the blood. Lipid and lipoprotein abnormalities are common in the general population, and are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. Primary dyslipidemia is usually due to genetic causes, while secondary dyslipidemia arises due to other underlying causes such as diabetes mellitus. Thus, dyslipidemia is an important factor in the development of atherosclerosis and cardiovascular diseases therefore, it is important to diagnose it in time. This review focuses on the modern methods of diagnosis of dyslipidemia.

Neuron density in the hippocampus in rat strains with contrasting nervous system excitability after prolonged emotional-pain stress.

A model system consisting of two rat strains bred for nervous system excitability in response to electric shocks was used to study changes in the number density of neurons in hippocampal field CA3 at 24 h, two weeks, and two and six months after prolonged emotional-pain stress (PEPS). Neuron density in hippocampal field CA3 decreased after completion of PEPS. These changes arose at different time points in the different rat strains (one day for low-excitability rats, two months for high-excitability rats) and persisted to six months. Thus, this is the first demonstration that persistent differential effects of stress on the number density of neurons in hippocampal field CA3, which plays an important role in learning and memory processes, depend on genetically determined constitutive characteristics of the nervous system.

[Numerical density of neurons in the hippocampus of rat lines contrasting in excitability of the nervous system exposed to prolonged emotional painful stress].

Two lines of rats, selected according to the excitability of nervous system to the action of an electric current, served as the model objects to study the changes of numerical density of neurons in hippocampus area CA3 24 hours, 2 weeks, 2 and 6 months after prolonged exposure to emotional painful stress. Reduction of neuron density in hippocampus area CA3 was demonstrated after exposure to stress that persisted as long as 6 months. These changes developed following time intervals that were different for each line of rats (24 hours for rats with low excitability and 2 month--for rats with high excitability). Thus, it was demonstrated for the first time, that prolonged differential effect of stress on numerical density of neurons in hippocampus area CA3, that plays an important role in the processes of learning and memory, depends on genetically determined constitutional peculiarities of the nervous system.