ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

Getz, Godfrey S.; Reardon, Catherine A.

doi:10.1194/jlr.r067249

Cited by 65 publications

(45 citation statements)

References 92 publications

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“…ApoE −/− mice on a HF diet or double KO mice for ApoE and LDL receptors are ideal mouse models for atherosclerosis (Ewart et al . ; Getz & Reardon, ). ApoE plays a role in the clearance of lipids from the blood stream; therefore, ApoE −/− mice on a HF diet exhibit extreme hyperlipidaemia.…”

Section: Vascular Function In Dyslipidaemiamentioning

confidence: 99%

Pulmonary vascular dysfunction in metabolic syndrome

Willson

Watanabe

Tsuji‐Hosokawa

2018

The Journal of Physiology

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Metabolic syndrome is a critically important precursor to the onset of many diseases, such as cardiovascular disease, and cardiovascular disease is the leading cause of death worldwide. The primary risk factors of metabolic syndrome include hyperglycaemia, abdominal obesity, dyslipidaemia, and high blood pressure. It has been well documented that metabolic syndrome alters vascular endothelial and smooth muscle cell functions in the heart, brain, kidney and peripheral vessels. However, there is less information available regarding how metabolic syndrome can affect pulmonary vascular function and ultimately increase an individual's risk of developing various pulmonary vascular diseases, such as pulmonary hypertension. Here, we review in detail how metabolic syndrome affects pulmonary vascular function.

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Section: Vascular Function In Dyslipidaemiamentioning

confidence: 99%

Pulmonary vascular dysfunction in metabolic syndrome

Willson

Watanabe

Tsuji‐Hosokawa

2018

The Journal of Physiology

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“…Thus, dietary manipulation of the content of methyl donors and B vitamins is an established approach to produce the accumulation of tHcy in mice, especially in the presence of an excess of methionine [12,20,21]. With this purpose, we fed genetically susceptible apolipoprotein E-deficient (ApoE −/− ) mice [22] a high-fat diet hypomethylating (HFLM) diet, or a high-fat control diet (HF) with a normal content of methyl donors. After confirming the presence of mild HHcy only in the HFLM-fed mice, we measured systemic inflammation, the plasma and aortic SAM:SAH ratio, and compared the extent of atherosclerotic lesions formation.…”

Section: Introductionmentioning

confidence: 99%

No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

et al. 2020

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Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (ApoE −/−) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation.

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“…Apoprotein E (ApoE) is a multifunctional protein that influences many aspects of cardiovascular physiology. ApoE −/− mice have also been extensively utilized as an atherosensitive platform [ 19 ]. In the present study, we found that treatment with NaHS (50 μM/kg/day, intraperitoneally) for 14 weeks significantly reduced the serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL) induced by high-cholesterol diet ( Figure 3 A), and alleviated atherogenesis (plaque areas) in ApoE −/− mice fed a high-cholesterol diet ( Figure 3 B,C, p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Hydrogen Sulfide Up-Regulates the Expression of ATP-Binding Cassette Transporter A1 via Promoting Nuclear Translocation of PPARα

Liu

Xiong

Peng

et al. 2016

IJMS

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ATP binding cassette transporter A1 (ABCA1) plays a key role in atherogenesis. Hydrogen sulfide (H2S), a gasotransmitter, has been reported to play an anti-atherosclerotic role. However, the underlying mechanisms are largely unknown. In this study we examined whether and how H2S regulates ABCA1 expression. The effect of H2S on ABCA1 expression and lipid metabolism were assessed in vitro by cultured human hepatoma cell line HepG2, and in vivo by ApoE−/− mice with a high-cholesterol diet. NaHS (an exogenous H2S donor) treatment significantly increased the expression of ABCA1, ApoA1, and ApoA2 and ameliorated intracellular lipid accumulation in HepG2 cells. Depletion of the endogenous H2S generator cystathionine γ-lyase (CSE) by small RNA interference (siRNA) significantly decreased the expression of ABCA1 and resulted in the accumulation of lipids in HepG2 cells. In vivo NaHS treatment significantly reduced the serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoproteins (LDL), diminished atherosclerotic plaque size, and increased hepatic ABCA1 expression in fat-fed ApoE−/− mice. Further study revealed that NaHS upregulated ABCA1 expression by promoting peroxisome proliferator-activated receptor α (PPARα) nuclear translocation. H2S up-regulates the expression of ABCA1 by promoting the nuclear translocation of PPARα, providing a fundamental mechanism for the anti-atherogenic activity of H2S. H2S may be a promising potential drug candidate for the treatment of atherosclerosis.

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ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

Cited by 65 publications

References 92 publications

Pulmonary vascular dysfunction in metabolic syndrome

Pulmonary vascular dysfunction in metabolic syndrome

No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

Hydrogen Sulfide Up-Regulates the Expression of ATP-Binding Cassette Transporter A1 via Promoting Nuclear Translocation of PPARα

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