Reduced alpha-lipoic acid synthase gene expression exacerbates atherosclerosis in diabetic apolipoprotein E-deficient mice

Objective— Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E–deficient mice and the underlying mechanism. Approach and Results— Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E–deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1 , and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. Conclusions— Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.

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Effect of alpha-lipoic acid on antioxidant gene expression and kidney injury in alloxan-induced diabetic rats

Journal of Nephropathology ◽

10.15171/jnp.2019.06 ◽

2018 ◽

Vol 8 (1) ◽

pp. 6-6 ◽

Cited By ~ 2

Author(s):

Parisa Jamor ◽

Hassan Ahmadvand ◽

Hesam Ashoory ◽

Esmaeel Babaeenezhad

Keyword(s):

Gene Expression ◽

Lipoic Acid ◽

Kidney Injury ◽

Diabetic Rats ◽

Pcr Analysis ◽

Control Group ◽

Diabetic Patients ◽

Alpha Lipoic Acid ◽

The Impact ◽

Gpx Activity

Background: Myeloperoxidase (MPO) is involved in the initiation, progression, and complications of atherosclerosis in diabetic patients. Objectives: In the current study, the impact of alpha-lipoic acid (LA), a natural antioxidant and a cofactor in the enzyme complexes on MPO, catalase (CAT) and glutathione peroxidase (GPx) activity, glutathione (GSH) and malondialdehyde (MDA) level, histopathology of kidney and expression of antioxidant enzymes, superoxide dismutase (SOD), GPx and CAT which are involved in the detoxification of reactive oxygen species (ROS), was evaluated in alloxan-induced diabetic rats. Materials and Methods: In this study, 30 male Rattus norvegicus rats randomly divided into three groups; control (C), non-treated diabetic (NTD), and LA-treated diabetics (LATD) was induced by alloxan monohydrate (100mg/kg; subcutaneous [SC]). Then treatment was performed with alphaLA (100 mg/kg intraperitoneal (i.p) daily to 6 weeks). Blood sample of animals collected to measure levels of MPO, CAT and GPx activity GSH and MDA. Kidney paraffin sections were prepared to estimate histological studies and to measure quantitative gene expression SOD, GPX and CAT in kidney. Results: Induction of diabetes led to a significant increase in MPO and MDA, reduced GSH level and GPx and CAT activities (P < 0.05). However, treatment with alpha-LA led to a significant elevation in GPx, CAT and GSH levels with a reduction in MPO activities and MDA levels (P < 0.05). Furthermore, the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis results showed increased expressions of GPx, CAT and SOD enzyme in the treatment group compared with the diabetic control group. Histopathological lesions such as increased glomerular volume and lymphocyte infiltration were attenuated in the alpha-LA treated group. Conclusions: Our findings indicated that alpha-LA supplementation is effective in preventing complications induced by oxidative stress and atherosclerosis in diabetic rats.

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Alpha-lipoic acid prevents arsenic toxicity in HepG2 cells by upregulation of GSH content, metabolic activity and HOX1 gene expression

Toxicology Letters ◽

10.1016/j.toxlet.2007.05.151 ◽

2007 ◽

Vol 172 ◽

pp. S47-S48

Author(s):

Selene Huerta-Olvera ◽

José Macías-Barragán ◽

Juan Armendáriz-Borunda ◽

Fernando Diaz-Barriga ◽

Fernando Siller-López

Keyword(s):

Gene Expression ◽

Metabolic Activity ◽

Lipoic Acid ◽

Hepg2 Cells ◽

Arsenic Toxicity ◽

Alpha Lipoic Acid

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Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.042683999 ◽

2002 ◽

Vol 99 (4) ◽

pp. 2234-2239 ◽

Cited By ~ 123

Author(s):

E. Trogan ◽

R. P. Choudhury ◽

H. M. Dansky ◽

J. X. Rong ◽

J. L. Breslow ◽

...

Keyword(s):

Gene Expression ◽

Apolipoprotein E ◽

Laser Capture Microdissection ◽

Atherosclerotic Lesions ◽

Laser Capture ◽

Deficient Mice

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Synthetic gestagens exert differential effects on arterial thrombosis and aortic gene expression in ovariectomized apolipoprotein E-deficient mice

British Journal of Pharmacology ◽

10.1111/bph.12814 ◽

2014 ◽

pp. n/a-n/a ◽

Cited By ~ 2

Author(s):

T Freudenberger ◽

R Deenen ◽

I Kretschmer ◽

A Zimmermann ◽

L F Seiler ◽

...

Keyword(s):

Gene Expression ◽

Apolipoprotein E ◽

Arterial Thrombosis ◽

Differential Effects ◽

Deficient Mice

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Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2009.12.004 ◽

2010 ◽

Vol 29 (2) ◽

pp. 144-149 ◽

Cited By ~ 23

Author(s):

Selene G. Huerta-Olvera ◽

José Macías-Barragán ◽

Martha E. Ramos-Márquez ◽

Juan Armendáriz-Borunda ◽

Fernando Díaz-Barriga ◽

...

Keyword(s):

Gene Expression ◽

Heme Oxygenase ◽

Lipoic Acid ◽

Hepg2 Cells ◽

Arsenic Exposure ◽

Alpha Lipoic Acid ◽

Nrf2 Activation

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Gene therapy of apolipoprotein E–deficient mice using a novel macrophage-specific retroviral vector

Blood ◽

10.1182/blood-2002-07-2131 ◽

2003 ◽

Vol 101 (2) ◽

pp. 485-491 ◽

Cited By ~ 47

Author(s):

Peter J. Gough ◽

Elaine W. Raines

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Gene Therapy ◽

Apolipoprotein E ◽

Human Gene ◽

Retroviral Vectors ◽

Retroviral Vector ◽

Hematopoietic Stem ◽

Human Gene Therapy ◽

Deficient Mice

The use of retroviral gene transfer into hematopoietic stem cells for human gene therapy has been hampered by the absence of retroviral vectors that can generate long-lasting, lineage-specific gene expression. We developed self-inactivating retroviral vectors that incorporate gene-regulatory elements from the macrophage-restricted human CD68 gene. Through the transplantation of transduced murine hematopoietic stem cells (HSCs), we show that a vector incorporating a 342–base pair (bp) fragment of 5′ flanking sequence from the CD68 gene, in addition to the CD68 first intron, was able to direct macrophage-specific expression of an enhanced green fluorescent protein (EGFP) reporter gene in inflammatory cell exudates and lymphoid organs in vivo. Levels of EGFP expression generated by this vector were greater than those generated by a standard Moloney murine leukemia retroviral vector, and they were stable for at least a year after transplantation of transduced HSCs. To evaluate the ability of this vector to generate therapeutically useful levels of gene expression, we transplanted apolipoprotein E (ApoE)–deficient HSCs transduced with a virus encoding ApoE into ApoE-deficient mice. Macrophages from these mice expressed levels of ApoE that were comparable to those from wild-type mice, and vector-driven expression of ApoE in macrophages was sufficient to reverse both hypercholesterolemia and atherosclerotic lesion development. The future application of this retroviral vector should provide a powerful tool to further elucidate macrophage function and for human gene therapy.

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