Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

Thampi, Prajitha; Stewart, Bradford W.; Joseph, Lija; Melnyk, Stepan; Hennings, Leah; Nagarajan, Shanmugam

doi:10.1016/j.atherosclerosis.2007.09.014

Cited by 45 publications

(40 citation statements)

References 49 publications

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“…Activation of LOX-1 with Ox-LDL induces cell injury in human coronary artery endothelial cells (ECs) (Morawietz, 2010). Expression of LOX-1 in atherosclerotic lesions was increased in mice fed a hypermethionine diet (Thampi et al, 2008). However, to our knowledge, precisely how Hcy affects LOX-1 expression in ECs remains unknown.…”

Section: Introductionmentioning

confidence: 96%

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

Yang¹,

Tian²,

J³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Homocysteine (Hcy) is an independent risk factor of atherosclerosis through its involvement with the methionine cycle. In this study, we aimed to determine the blood vessel global methylation rate in Hcy-induced atherosclerosis in apolipoprotein-E-deficient (ApoE -/-) mice, and to explore the possible mechanism of this change in endothelial cells. ApoE -/-mice were divided into a hyperlipidemia (HLP) group, a hyperhomocysteinemia (HHcy) group, and an HHcy + folate + vitamin B12 (HHcy+FA+VB) group. Wild-type C57BL/6J mice were prepared as controls. Total Hcy, lipids, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) contents in serum were measured with an automatic biochemistry analyzer and high-performance liquid chromatography. Methylation of B1 repetitive elements in blood vessels was tested using nested methylation-specific-polymerase chain reaction (nMS-PCR). Endothelial cells (ECs) were pretreated with Hcy or by adding FA and VB. Lectin-like oxidized LDL receptor-1 (LOX-1) expressions were determined by quantitative PCR, Western blot, and nMS-PCR. The HHcy group displayed severe HLP and HHcy. SAM and SAH contents were also elevated in the HHcy group compared with other groups. Methylation of B1 repetitive elements was significantly increased in the HHcy group (0.5050 ± 0.0182) compared to the HLP (0.5158 ± 0.0163) and control (0.5589 ± 0.0236) groups. mRNA and protein expressions of LOX-1 increased (0.2877 ± 0.0341, 0.6090 ± 0.0547), whereas methylation expression decreased (0.5527 ± 0.0148) after 100 µM Hcy stimulation in ECs. In conclusion, Hcy-induced atherosclerosis was closely associated with induced hypomethylation status in the blood vessel, and this process was partially mediated by LOX-1 DNA methylation.

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Section: Introductionmentioning

confidence: 96%

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

Yang¹,

Tian²,

J³

et al. 2014

Genet. Mol. Res.

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“…37 Several other investigators, using a variety of dietary and genetic approaches to induce hyperhomocysteinemia in Apoe Ϫ/Ϫ mice, have confirmed and extended the observations of Hofmann. 46,56,57,85,86 An interesting study by Troen et al suggested that a high dietary intake of methionine may be atherogenic in Apoe Ϫ/Ϫ mice, even in the absence of significant hyperhomocysteinemia. 36 Taken together, the vascular phenotypes observed in multiple murine models of hyperhomocysteinemia strongly suggest that hyperhomocysteinemia, whether induced by dietary or genetic approaches, is a causative factor in the development of atherothrombotic vascular disease.…”

Section: Vascular Phenotypes Of Hyperhomocysteinemic Micementioning

confidence: 99%

“…56,57 The addition of 0.9 g/L homocystine (the disulfide derivative of L-homocysteine) produced a lesser elevation of plasma tHcy (16 mol/L) 57 (Table 1). In another study, 46 …”

Section: Dietary Administration Of Homocysteinementioning

confidence: 99%

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Dayal

Lentz

2008

ATVB

103

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Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine β -synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.

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“…Hcy has been investigated as a risk factor for cardiovascular disease since 1969, when McCully observed that two patients with homocystinuria were affected with extensive atherosclerosis and arterial thrombosis [2]. Since the association between elevated level of Hcy and increased risk of coronary heart disease was established [3,4], the issue whether there is a causal relation still remains unclear [5,6].…”

Section: Introductionmentioning

confidence: 99%

Serum homocysteine levels are decreased in levothyroxine-treated women with autoimmune thyroiditis

Owecki

Dorszewska

Sawicka‐Gutaj

et al. 2014

EJEA

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Background: Hyperhomocysteinemia is a well-known cardiovascular risk factor and its elevation is established in overt hypothyroidism. Since some authors suggest that chronic autoimmune thyroiditis per se may be considered as a novel risk factor of atherosclerosis independent of thyroid function, the analysis of classical cardiovascular risk factors might be helpful in evaluation the causative relationship. Data concerning the impact of thyroid autoimmunity in euthyroid state on homocysteine (Hcy) level is lacking. The aim of this study was to evaluate Hcy level in context of anti-thyroperoxidase antibodies (TPOAbs) in euthyroidism. Methods: It is a case-control study. 31 euthyroid women treated with levothyroxine (L-T4) due to Hashimoto thyroiditis (HT) and 26 females in euthyroidism without L-T4 replacement therapy were enrolled in the study. All women with HT had positive TPOAbs. Forty healthy females negative for TPOAbs comparable for age and body mass index (BMI) participated in the study as controls. Exclusion criteria were a history of any acute or chronic disease, use of any medications (including oral contraceptives and vitamin supplements), smoking, alcoholism. Results: TPOAbs titers were higher in both groups of HT patients versus the healthy controls. Hcy levels were found to be significantly lower in treated HT patients (Me 11 μmol; IQR 4.2 μmol) as compared with healthy controls (Me 13.35 μmol; IQR 6.34 μmol; p = 0.0179). In contrast, no significant difference was found between non treated HT and control group in Hcy level. The study groups and the controls did not differ in age and BMI. Furthermore, levels of TSH, FT4, TC, LDL, HDL and TAG did not differ between the study group and the control group. Conclusion: The main finding of the study is a decrease in Hcy level in treated HT as compared with healthy controls. Based on our observations one can also assume that correct L-T4 replacement was associated here with a decrease of Hcy. Furthermore, it seems that non treated HT in euthyroidism is not associated with Hcy increase, in contrast to overt hypothyroidism. This may be just another argument against the concepts about the role of "euthyroid HT" in the development of atherosclerosis.

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Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

Cited by 45 publications

References 49 publications

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

Homocysteine induces blood vessel global hypomethylation mediated by LOX-1

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Serum homocysteine levels are decreased in levothyroxine-treated women with autoimmune thyroiditis

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