Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Dayal, Sanjana; Lentz, Steven R.

doi:10.1161/atvbaha.108.166421

Cited by 102 publications

(109 citation statements)

References 98 publications

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“…26 In this study, mice were fed a diet with drinking water supplemented with 2% L-methionine. After 3 months on the diet, mice demonstrated an approximately eightfold increase in plasma levels of homocysteine compared with control mice fed a normal diet (24.4 Ϯ 2.9 versus 2.9 Ϯ 0.4 mol/L, respectively) ( Figure 1).…”

Section: Hyperhomocysteinemia Suppresses Liver Regeneration After Parmentioning

confidence: 99%

Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

Liu

Zhao

Gao

et al. 2010

The American Journal of Pathology

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Elevated homocysteine levels are defined as hyperhomocysteinemia (HHcy), a disorder that is associated with cardiovascular and neurodegenerative diseases as well as with hepatic fibrosis. Recent studies have shown that HHcy promotes hepatic injury by increasing oxidative stress. Although homocysteine induces cell cycle arrest in a variety of different cell types, it is not known whether HHcy has a definitive role in hepatocyte proliferation during liver regeneration. In this report, we investigated the effect of homocysteine on liver regeneration. Our results demonstrated that mice with HHcy exhibited an impairment in liver regeneration after partial hepatectomy, as measured by immunohistochemical staining of proliferation cell nuclear antigen and bromodeoxyuridine incorporation. Impaired proliferation was also correlated with reduced cyclin D1 induction and elevated expression levels of both p53 and p21 Cip1. In addition, the phosphorylation of Akt, which plays an essential role in normal regeneration responses, was attenuated during the early phases of liver regeneration in HHcy mice. Our results also indicated that the cAMP/protein kinase A pathway mediated the inhibitory effect of homocysteine on liver regeneration. These findings provide evidence that impairment of liver regeneration by HHcy may result in delayed recovery from liver injury induced by homocysteine itself. (Am J

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Section: Hyperhomocysteinemia Suppresses Liver Regeneration After Parmentioning

confidence: 99%

Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

Liu

Zhao

Gao

et al. 2010

The American Journal of Pathology

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“…In addition, animal models of hyperhomocysteinaemia have shown abnormalities of vascular structure and function (4) . Paradoxically, however, clinically controlled trials failed to show that lowering homocysteine with vitamin B therapy as secondary prevention reduced risk of CVD or mortality (5 -7) .…”

Section: Homocysteine: B-vitamins: Cystatin C: Inflammation: Atheroscmentioning

confidence: 99%

Cystatin C levels in plasma and peripheral blood mononuclear cells among hyperhomocysteinaemic subjects: effect of treatment with B-vitamins

et al. 2009

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Homocysteine has been related to increased risk of CVD. Matrix degradation and inflammation may be involved in this link between hyperhomocysteinaemia and CVD. Recent studies suggest that cystatin C can modulate matrix degradation and inflammation. The present study measured cystatin C at protein (plasma) and mRNA levels (peripheral blood mononuclear cells (PBMC)) in hyperhomocysteinaemic individuals (n 37, female seven and male thirty, aged 20-70 years) before and after B-vitamin supplementation for 3 months in a randomised, placebo-controlled double-blind trial. In a cross-sectional study, seventeen of the hyperhomocysteinaemic subjects were age-and sex-matched to healthy controls (n 17). Our main findings were: (i) as compared with controls, hyperhomocysteinaemic subjects tended to have higher plasma concentrations of cystatin C and lower mRNA levels of cystatin C in PBMC; (ii) compared with placebo, treatment of hyperhomocysteinaemic individuals with B-vitamins significantly increased plasma levels of cystatin C and mRNA levels of cystatin C in PBMC; (iii) while plasma levels of cystatin C were positively correlated with plasma levels of TNF receptor-1, mRNA levels of cystatin C in PBMC were inversely correlated with this TNF parameter. Taken together, our findings suggest that disturbed cystatin C levels may be a characteristic of hyperhomocysteinaemic individuals, potentially related to low-grade systemic inflammation in hyperhomocysteinaemic subjects, and that B-vitamins may modulate cystatin C levels in these individuals. Homocysteine: B-vitamins: Cystatin C: Inflammation: AtherosclerosisEpidemiological studies have established that elevated plasma levels of homocysteine are associated with an increased risk of ischaemic stroke, myocardial infarction and venous thromboembolism (1 -3) . In addition, animal models of hyperhomocysteinaemia have shown abnormalities of vascular structure and function (4) . Paradoxically, however, clinically controlled trials failed to show that lowering homocysteine with vitamin B therapy as secondary prevention reduced risk of CVD or mortality (5 -7) . In contrast, the recently reported improvement in stroke mortality observed after folic acid fortification in the United States and Canada, but not in England and Wales (where fortification is not mandatory), is consistent with the hypothesis that folic acid fortification helps to reduce deaths from stroke (8) . These findings are supported by a recent meta-analysis, showing that folic acid supplementation can effectively reduce the risk of stroke in primary prevention (9) . Thus, the homocysteine hypothesis in CVD is not dead (10) , and the precise mechanism by which hyperhomocysteinaemia is related to atherogenesis needs to be further elucidated.Inflammation and matrix degradation play important roles in the pathogenesis of atherosclerosis and plaque destabilisation. Previously, we have shown that hyperhomocysteinaemic subjects are characterised by raised serum levels of inflammatory cytokines and matrix metalloproteinases...

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“…Generally, mild HHcy can be induced by increasing total methionine. 23 The animals were fed one of the following two diets 1 : control diet (LM-485 chow; Harlan Teklad, Madison, WI) 2 or a high-methionine diet (LM-485 chow with drinking water supplemented with two percent L-methionine). Mice were sacrificed after three months on the diets.…”

Section: Induction Of Hhcymentioning

confidence: 99%

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

Liu

et al. 2011

The American Journal of Pathology

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Recently, epidemiological and experimental studies have linked hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs glucose homeostasis by affecting glycogenesis in the liver is not clear. In the present study, we investigated the effect of HHcy on hepatic glycogen synthesis. Hyperhomocysteinemia was induced in mice by drinking water containing two percent methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen synthase and a significant decrease in hepatic glycogen content and the rate of glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was up-regulated in the liver of mice with HHcy, concomitantly with the dephosphorylation of glycogen synthase kinase-3␤ and Akt. The knockdown of TRB3 by short hairpin RNA suppressed the dephosphorylation of these two kinases. Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response element-binding protein phosphorylation, which in turn up-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1␣ and TRB3. The inhibition of PPAR-␣ by its inhibitor, MK886, or knockdown of PPAR-␣ by small interfering RNA significantly inhibited the expression of TRB3 induced by homocysteine. The current study demonstrates that HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3. These results provide a novel explanation for the development and progression of insulin resistance in HHcy.

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Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Cited by 102 publications

References 98 publications

Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

Cystatin C levels in plasma and peripheral blood mononuclear cells among hyperhomocysteinaemic subjects: effect of treatment with B-vitamins

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

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