Modified lipoproteins as biomarkers of atherosclerosis

Orekhov, Alexander N.; Собенин, И.А.

doi:10.2741/4653

Cited by 26 publications

(43 citation statements)

References 41 publications

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“…It is generally accepted that the source of cholesterol accumulation is modified LDL [35,36]. Atherogenic multiple-modified LDL that can cause the accumulation of intracellular lipids [3,16,17] circulate in the blood of atherosclerotic patients.…”

Section: Discussionmentioning

confidence: 99%

“…Atherogenic modifications of LDL that have been described so far include acetylation, desialylation, maleylation, succinylation, oxidation by ions of metals of variable valence, treatment with formaldehyde, malondialdehyde, phospholipase A2, C, and D, etc. [9][10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Multiple modified LDL species can be found in the circulation of atherosclerotic patients [3,16,17]. Noteworthy, atherogenic modification of LDL is not limited to oxidation.…”

Section: Introductionmentioning

confidence: 99%

“…Misconceptions about the key role of oxidized LDL in the formation of foam cells are widespread. However, alteration of other physical-chemical characteristics of the lipid, protein, and glycoconjugate moieties of lipoprotein particles have been revealed [16,17]. Oxidation appears to be neither the primary nor the only atherogenic modification of LDL.…”

Section: Introductionmentioning

confidence: 99%

“…The key mechanism of interaction between modified LDL and macrophages are recognition and internalization via scavenger receptors. This leads to lipid accumulation and foam cell formation [3,16,17]. Notably, macrophages are not the only source of foam cells.…”

Section: Introductionmentioning

confidence: 99%

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Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our Int.Int. J. Mol. Sci. 2020, 21, 2716 2 of 17 group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Multiple modified LDL species can be found in the circulation of atherosclerotic patients [3,16,17]. Noteworthy, atherogenic modification of LDL is not limited to oxidation.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Natural products: The role and mechanism in low‐density lipoprotein oxidation and atherosclerosis

Zhang

Chen

et al. 2020

Phytotherapy Research

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Atherosclerosis is a chronic inflammatory, metabolic, and epigenetic disease, which leads to the life-threatening coronary artery disease. Emerging studies from bench to bedside have demonstrated the pivotal role of low-density lipoprotein (LDL) oxidation in the initiation and progression of atherosclerosis. This article hereby reviews oxidation mechanism of LDL, and the pro-atherogenic and biomarker role of oxidized LDL in atherosclerosis. We also review the pharmacological effects of several representative natural products (vitamin E, resveratrol, quercetin, probucol, tanshinone IIA, epigallocatechin gallate, and Lycopene) in protecting against LDL oxidation and atherosclerosis. Clinical and basic research supports the beneficial effects of these natural products in inhibiting LDL oxidation and preventing atherosclerosis, but the data are still controversial. This may be related to factors such as the population and the dosage and time of taking natural products involved in different studies. Understanding the mechanism of LDL oxidation and effect of oxidized LDL help researchers to find novel therapies against atherosclerosis.

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6-methylcoumarin/miR-122 suppresses hepatic Sortilin-mediated ApoB-100 secretion to attenuate aortic atherosclerosis

Ming,

Chen,

et al. 2024

Cellular Signalling

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Modified lipoproteins as biomarkers of atherosclerosis

Cited by 26 publications

References 41 publications

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Natural products: The role and mechanism in low‐density lipoprotein oxidation and atherosclerosis

6-methylcoumarin/miR-122 suppresses hepatic Sortilin-mediated ApoB-100 secretion to attenuate aortic atherosclerosis

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