Mechanisms Underlying Atheroma Induction: The Roles of Mechanotransduction, Vascular Wall Cells, and Blood Cells

Novikova, Olga A.; Laktionov, Pavel P.; Карпенко, А. А.

doi:10.1016/j.avsg.2018.04.030

Cited by 6 publications

(10 citation statements)

References 84 publications

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“…80 Aggrecan has been shown by immunostaining to be present in both stable and unstable advanced plaques, including calcified lesions, in both human and mice. 81,82 Several studies have attempted to identify the cells responsible for aggrecan production in atherosclerotic lesions as well as the underlying mechanisms driving its expression. VSMCs, specifically pericytes, can display chondrocyte-like biosynthesis in response to BMP-2 and Wnts and produce aggrecan as part of an intermediate phenotype.…”

Section: Atherosclerosismentioning

confidence: 99%

“…80 Aggrecan has been shown by immunostaining to be present in both stable and unstable advanced plaques, including calcified lesions, in both human and mice. 81,82…”

Section: Aggrecan In Cardiovascular Diseasementioning

confidence: 99%

“…80 Aggrecan has been shown by immunostaining to be present in both stable and unstable advanced plaques, including calcified lesions, in both human and mice. 81,82 VSMCs or derivatives from the VSMC lineage arising by phenotypic modulation are the primary source of aggrecan in atherosclerosis. Aggrecan accumulation promotes VSMC apoptosis in atherosclerotic plaques.…”

Section: Summary Of Main Findingsmentioning

confidence: 99%

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Aggrecan in Cardiovascular Development and Disease

Koch

Lee

Apte

2020

J Histochem Cytochem.

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Aggrecan is a large proteoglycan that forms giant hydrated aggregates with hyaluronan in the extracellular matrix (ECM). The extraordinary resistance of these aggregates to compression explains their abundance in articular cartilage of joints where they ensure adequate load-bearing. In the brain, they provide mechanical buffering and contribute to formation of perineuronal nets, which regulate synaptic plasticity. Aggrecan is also present in cardiac jelly, developing heart valves, and blood vessels during cardiovascular development. Whereas aggrecan is essential for skeletal development, its function in the developing cardiovascular system remains to be fully elucidated. An excess of aggrecan was demonstrated in cardiovascular tissues in aortic aneurysms, atherosclerosis, vascular re-stenosis after injury, and varicose veins. It is a product of vascular smooth muscle and is likely to be an important component of pericellular matrix, where its levels are regulated by proteases. Aggrecan can contribute to specific biophysical and regulatory properties of cardiovascular ECM via the diverse interactions of its domains, and its accumulation is likely to have a significant role in developmental and disease pathways. Here, the established biological functions of aggrecan, its cardiovascular associations, and potential roles in cardiovascular development and disease are discussed.

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Section: Atherosclerosismentioning

confidence: 99%

“…80 Aggrecan has been shown by immunostaining to be present in both stable and unstable advanced plaques, including calcified lesions, in both human and mice. 81,82…”

Section: Aggrecan In Cardiovascular Diseasementioning

confidence: 99%

Section: Summary Of Main Findingsmentioning

confidence: 99%

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Aggrecan in Cardiovascular Development and Disease

Koch

Lee

Apte

2020

J Histochem Cytochem.

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“…We searched for the nodes in the global signal transduction network that may potentially regulate the activity of the set of TFs identified at the previous step of the analysis. We computed a key-node score for each of such nodes according to the formula described in our previous publication [2]. The key-node score ranked the identified nodes according to their potential impact on the activity of the identified TFs.…”

Section: Identification Of Master Regulators In the Signal Transductimentioning

confidence: 99%

“…Intracellular lipid accumulation can be regarded as a trigger event in atherogenesis at the cellular level. In turn, lipid accumulation stimulates the main atherogenic manifestations in the arterial wall, including increased cell proliferation, extracellular matrix production, and the loss of intercellular contacts [1][2][3]. According to the current understanding, circulating low-density lipoprotein (LDL) is the main source of lipids accumulating in the arterial wall cells.…”

Section: Introductionmentioning

confidence: 99%

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

Orekhov

Nikiforov

Sukhorukov

et al. 2020

IJMS

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Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, 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. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.

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