The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis

Summerhill, Volha I; Grechko, Andrey V.; Yet, Shaw‐Fang; Собенин, И.А.; Orekhov, Alexander N.

doi:10.3390/ijms20143561

Cited by 103 publications

(76 citation statements)

References 87 publications

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“…We have previously shown that lipid accumulation within the arterial cells is the trigger that initiates the activation of cellular functions associated with atherogenesis [34]. 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%

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.

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Section: Discussionmentioning

confidence: 99%

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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“…Although LDL is currently recognized as the main source of intracellular lipid accumulation in the plaque, native LDL particles do not cause prominent lipid accumulation in cultured cells; hence, they do not possess atherogenicity. It is atherogenic modification of LDL, which alters the physical-chemical characteristics of LDL particles, that triggers massive lipid accumulation [3]. A cascade of multiple modifications of LDL has been proposed as a plausible model for LDL atherogenic modification in the blood.…”

Section: Dyslipidemia In Diabetic Patientsmentioning

confidence: 99%

“…Atherosclerosis is classically associated with altered lipid metabolism and hypercholesterolemia [2]. An elevated level of circulating modified low-density lipoprotein (LDL) is a known risk factor of cardiovascular diseases [3]. However, the disease pathogenesis appears to be more complex than lipid metabolism changes and involves multiple factors, the most prominent of which is inflammation [4].…”

Section: Introductionmentioning

confidence: 99%

The Diabetes Mellitus–Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation

Poznyak

Grechko

Poggio

et al. 2020

IJMS

559

359

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Diabetes mellitus comprises a group of carbohydrate metabolism disorders that share a common main feature of chronic hyperglycemia that results from defects of insulin secretion, insulin action, or both. Insulin is an important anabolic hormone, and its deficiency leads to various metabolic abnormalities in proteins, lipids, and carbohydrates. Atherosclerosis develops as a result of a multistep process ultimately leading to cardiovascular disease associated with high morbidity and mortality. Alteration of lipid metabolism is a risk factor and characteristic feature of atherosclerosis. Possible links between the two chronic disorders depending on altered metabolic pathways have been investigated in numerous studies. It was shown that both types of diabetes mellitus can actually induce atherosclerosis development or further accelerate its progression. Elevated glucose level, dyslipidemia, and other metabolic alterations that accompany the disease development are tightly involved in the pathogenesis of atherosclerosis at almost every step of the atherogenic process. Chronic inflammation is currently considered as one of the key factors in atherosclerosis development and is present starting from the earliest stages of the pathology initiation. It may also be regarded as one of the possible links between atherosclerosis and diabetes mellitus. However, the data available so far do not allow for developing effective anti-inflammatory therapeutic strategies that would stop atherosclerotic lesion progression or induce lesion reduction. In this review, we summarize the main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship with chronic inflammation. We also discuss the established pathophysiological features that link atherosclerosis and diabetes mellitus, such as oxidative stress, altered protein kinase signaling, and the role of certain miRNA and epigenetic modifications.

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“…The emergence of the foam cells in the arterial intima is considered to be one of the earliest manifestations of atherosclerosis, referring to the preclinical atherogenesis. Moreover, the underlying extra-and intracellular lipid deposition is a crucial trigger of atherosclerotic lesion development [16,17].…”

Section: The Origin Of Foam Cellsmentioning

confidence: 99%

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Poznyak

Melnichenko

et al. 2020

Cells

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Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

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The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis

Cited by 103 publications

References 87 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?

The Diabetes Mellitus–Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

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