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

Abstract

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.

Coenzyme Q homeostasis in aging: Response to non-genetic interventions

“…Other studies have also demonstrated that ubiquinol content in LDLs is the key factor influencing LDL susceptibility to oxidation [99]. Remarkably, the type of LDL capable of inducing the accumulation of cholesteryl esters in cells of the human aortic intima and originate atherosclerosis, known as multiple-modified low density lipoproteins [100], show high levels of oxidized CoQ10 and lower concentration of α-tocopherol [101] indicating a low capacity to preventing lipid peroxidation.…”

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

“…The molecular weight of this enzyme is 65 kDa, and it has three optimum pHs: 3.0, 5.0, and 7.0. It can act in the blood and cellular organelles with a lower pH (for example, inside the lysosome) ( 22 ). Trans-sialidase can cleave sialic acids from LDL, VLDL, IDL, and high-density lipoproteins (HDL).…”

Trained Circulating Monocytes in Atherosclerosis: Ex Vivo Model Approach

“…In this model, patients with atherosclerosis were given an investigational drug, and blood samples were collected at 0, 2, and 4 h. Monocytes were isolated from blood samples taken before the drug administration (0 hours) and after 2 and 4 h. After that, monocytes were cultivated in the presence of a pro-inflammatory activator (most often IFNγ, less often LPS) for 24 h, after which the TNFα expression in stimulated and non-stimulated cells was measured. In parallel, serum was isolated from blood samples, which were tested for their ability to induce the accumulation of cholesterol in cultured control monocytes isolated from the blood of healthy donors (Nikiforov et al, 2017c). Usually, blood serum of patients with atherosclerosis is atherogenic, i.e., causes the accumulation of cholesterol in cultured monocytes when added at 10% for 24 h. Blood serum of healthy donors, which did not exhibit atherogenic effect, was used as a control (Orekhov et al, 2014).…”