Salusin-β induces foam cell formation and monocyte adhesion in human vascular smooth muscle cells via miR155/NOX2/NFκB pathway

Objective: Foam cell formation is a characteristic of atherosclerotic lesions. It’s known that high glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects. Methods and Results: The results showed that high glucose in cultured human aortic SMCs increased the mRNA and protein expressions of CD36, a regulator of lipid influx, and suppressed the mRNA and protein expressions of ATP binding cassette (ABC) transporters ABCG1, a regulator of cholesterol efflux to HDL, in a dose- and time-dependent manner. However, the ability of cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose were easily developed into lipid-loaded cells as demonstrated by oil red O staining. Meanwhile, it had a maximum 2.3-fold increase in accumulation of esterified cholesterol compared to VSMCs cultured in normal glucose. Additionally, there was no change found in either liver X receptor (LXR)α or LXRβ, suggesting that high glucose-induced down-regulation of ABCG1 was LXR-independent. Down-regulation of ABCG1 induced by high glucose was almost totally reversed by the NF-κB inhibitors BAY 11–7085, tosyl-phenylalanine chloromethyl-ketone (TPCK) and by the antioxidant N-acetyl-L-cysteine(NAC). This reversal was accompanied by reduced intracellular lipid content. Furthermore, we also demonstrated that high glucose enhanced the binding of nuclear proteins extracted from human VSMCs to the NF-κB regulatory elements. This effect was abrogated by NAC and NF-κB inhibitors. Conclusions: These results suggested that hyperglycemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36 mediated modified LDL uptake and reducing ABCG1 regulated intracellular cholesterol efflux. Moreover, this effect was associated with activated NF-κB pathway signaling.

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Mechanism of foam cell formation by intimal smooth muscle cells through getting expression of VLDL receptor

Atherosclerosis ◽

10.1016/0021-9150(95)96349-w ◽

1995 ◽

Vol 115 ◽

pp. S25

Author(s):

I. Itsuko ◽

H. Kawachi ◽

S. Hirose ◽

N. Morisaki ◽

T. Yamamoto ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Foam Cell ◽

Cell Formation ◽

Muscle Cells ◽

Foam Cell Formation ◽

Vldl Receptor

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Enzymatically Modified Low-Density Lipoprotein Promotes Foam Cell Formation in Smooth Muscle Cells via Macropinocytosis and Enhances Receptor-Mediated Uptake of Oxidized Low-Density Lipoprotein

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.116.307306 ◽

2016 ◽

Vol 36 (6) ◽

pp. 1101-1113 ◽

Cited By ~ 34

Author(s):

Bijoy Chellan ◽

Catherine A. Reardon ◽

Godfrey S. Getz ◽

Marion A. Hofmann Bowman

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Muscle Cells ◽

Foam Cell Formation ◽

Low Density ◽

Oxidized Low Density Lipoprotein

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Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis

AJP Cell Physiology ◽

10.1152/ajpcell.00170.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. C707-C714 ◽

Cited By ~ 43

Author(s):

Qiangjun Cai ◽

Linda Lanting ◽

Rama Natarajan

Keyword(s):

Smooth Muscle ◽

Growth Factors ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Foam Cell Formation ◽

Ang Ii ◽

Signal Transduction Inhibitors ◽

Cox 2

Adhesive interactions between monocytes and vascular smooth muscle cells (VSMC) may contribute to subendothelial monocyte-macrophage retention in atherosclerosis. We investigated the effects of angiotensin II (ANG II) and platelet-derived growth factor (PDGF)-BB on VSMC-monocyte interactions. Treatment of human aortic VSMC (HVSMC) with ANG II or PDGF-BB significantly increased binding to human monocytic THP-1 cells and to peripheral blood monocytes. This was inhibited by antibodies to monocyte β1- and β2-integrins. The binding was also attenuated by blocking VSMC arachidonic acid (AA) metabolism by inhibitors of 12/15-lipoxygenase (12/15-LO) or cyclooxygenase-2 (COX-2). Conversely, binding was enhanced by overexpression of 12/15-LO or COX-2. Direct treatment of HVSMC with AA or its metabolites also increased binding. Furthermore, VSMC derived from 12/15-LO knockout mice displayed reduced binding to mouse monocytic cells relative to genetic control mice. Using specific signal transduction inhibitors, we demonstrated the involvement of Src, phosphoinositide 3-kinase, and MAPKs in ANG II- or PDGF-BB-induced binding. Interestingly, after coculture with HVSMC, THP-1 cell surface expression of the scavenger receptor CD36 was increased. These results show for the first time that growth factors may play additional roles in atherosclerosis by increasing monocyte binding to VSMC via AA metabolism and key signaling pathways. This can lead to monocyte subendothelial retention, CD36 expression, and foam cell formation.

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The miR-378c-Samd1 circuit promotes phenotypic modulation of vascular smooth muscle cells and foam cells formation in atherosclerosis lesions

Scientific Reports ◽

10.1038/s41598-021-89981-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shengya Tian ◽

Yang Cao ◽

Jinliang Wang ◽

Yongjun Bi ◽

Jingquan Zhong ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Transcriptional Repressor ◽

Muscle Cells ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Coronary Syndrome ◽

Phenotypic Transition

AbstractMicroRNAs have emerged as key regulators in vascular diseases and are involved in the formation of atherosclerotic lesions. However, the atherosclerotic-specific MicroRNAs and their functional roles in atherosclerosis are unclear. Here, we report that miR-378c protects against atherosclerosis by directly targeting Sterile Alpha Motif Domain Containing 1 (Samd1), a predicted transcriptional repressor. miR-378c was strikingly reduced in atherosclerotic plaques and blood of acute coronary syndrome (ACS) patients relative to healthy controls. Suppression of miR-378c promoted vascular smooth muscle cells (VSMCs) phenotypic transition during atherosclerosis. We also reported for the first time that Samd1 prolonged immobilization of LDL on the VSMCs, thus facilitated LDL oxidation and subsequently foam cell formation. Further, we found that Samd1 contains predicted DNA binding domain and directly binds to DNA regions as a transcriptional repressor. Together, we uncovered a novel mechanism whereby miR-378c-Samd1 circuit participates in two key elements of atherosclerosis, VSMCs phenotypic transition and LDL oxidation. Our results provided a better understanding of atherosclerosis pathophysiology and potential therapeutic management by targeting miR-378c-Samd1 circuit.

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