Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE&amp;lt;sup&amp;gt;&amp;minus;/&amp;minus;&amp;lt;/sup&amp;gt; mice

Ma, Shengchao; Zhang, Huiping; Sun, Weiwei; Gong, Huihui; Wang, Yanhua; Ma, Chao; Ju, Wang; Cao, Cong; Yang, Xia; Tian, Jianwei; Jiang, Yideng

doi:10.1093/abbs/gmt030

Cited by 33 publications

(22 citation statements)

References 34 publications

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“…We found that the expressions of gene associated with p53-apoptosis pathway, including TP53, Bax, Bcl2, Mcl1, caspase 3, MDM2, and ATM, were changed in heart of ApoE –/– mice. These results were consistent with the recent study [58], which demonstrated that the higher expressions of p53 and caspase-3/9 in heart of ApoE –/– mice. We also demonstrated that the percentages of apoptotic myocytes and apoptotic cells in the heart of ApoE -/- mice were significantly higher than those of wild-type mice at 16 weeks, and were suppressed after the treatment of AST-IV.…”

Section: Discussionsupporting

confidence: 94%

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

Ding²,

et al. 2017

Cell Physiol Biochem

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Background: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV) possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. Methods: The ApoE^-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67), senescence (p16^INK4a), oxidant (NADPH oxidase 4, NOX4) and antioxidant (superoxide dismutase, SOD) were observed by immunofluorescence staining. Results: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE^-/- mice. However, the decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS) in ApoE^–/– mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE^-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16^INK4a in the hearts of ApoE^-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. Conclusion: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.

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Section: Discussionsupporting

confidence: 94%

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

Ding²,

et al. 2017

Cell Physiol Biochem

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“…Increasing evidence has indicated that Hcy may be involved in the disturbance of the expression of AS-associated genes through the interference of DNA methylation (9). The metabolism of Hcy is specifically involved in the methionine cycle for transmethylation reactions, therefore, its elevation has been implicated in the interference of DNA methylation modification and the epigenetic regulation of genes (10).…”

Section: Fabp4-mediated Homocysteine-induced Cholesterol Accumulationmentioning

confidence: 99%

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

Jiang

Zhang

et al. 2016

Molecular Medicine Reports

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Abstract. Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages. Hcy concentrations of 0, 50, 100, 200 and 500 µM, and 100 µM Hcy+30 µM vitamin B 12 (VB 12 )+30 µM folic acid (FA) were respectively added to cultured THP-1 monocyte-derived macrophages for 24 h. The levels of FABP4, which acts as a key factor connecting cellular lipid accumulation to inflammation, were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in the macrophages. The present study used a nested touchdown methylation-specific PCR assay to detect the DNA methylation status of the FABP4 promoter region. In addition, the FABP4 gene fragment was inserted into the cloning vector, pcDNA3.1-EGFP, to construct the recombinant plasmid, pcDNA3.1-EGFP/FABP4, which was identified using restriction endonuclease digestion analysis and DNA sequencing. The pcDNA3.1-EGFP/FABP4 expression plasmid was transfected into THP-1 monocyte-derived macrophages, mediated by liposome reagent, following which the expression levels of FABP4 were detected using RT-qPCR and western blot analyses. The present study also determined the intracellular accumulation of total cholesterol in the macrophages. The results indicated that Hcy decreased the levels of FABP4 promoter methylation, but increased the mRNA and protein expression levels of FABP4 in the macrophages, compared with the control group (0 µM Hcy). However, no dose-dependent changes were observed with increasing concentrations of Hcy. The recombinant fluorescent eukaryotic expression vector, pcDNA3.1-EGFP/FABP4, was successfully constructed and effectively expressed in the THP-1 macrophages. The results also showed that FABP4 accelerated the accumulation of cholesterol in the macrophages. Taken together, the results of the present study suggested that FABP4 DNA hypomethylation induced by Hcy may be involved in the overexpression of FABP4, thereby inducing cholesterol accumulation in macrophages.

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“…Similarly Wang et al [41] showed that mir874 targets caspase 8 and hence regulates myocardial necrosis. Hyperhomocysteinemia induces cardiac injury by upregulation of the apoptosis-related genes that involve caspases 3 and 9 [42]. Yang et al [43] have proposed inhibition of caspase 3 which is a major executor of apoptosis, as a selective target for heart failure.…”

Section: Heart Fail Revmentioning

confidence: 99%

Resuscitation of a dead cardiomyocyte

2015

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Although cardiac resuscitation can revive the whole body, the mechanisms are unclear. To this end, we propose that reviving a dead/dysfunctional cardiomyocyte will shed light on resuscitation mechanisms and pave the way to treat cardiac myopathies. The degradation of the myocyte cytoskeleton by the proteasome system which involves calpains, ubiquitin, caspases and matrix metalloproteases is the main focus of this review. The activation of calpains beyond the calpastatin-mediated inhibition due to extensive calcium harbor can lead to titin degradation, damage to the sarcomere and contractile dysfunction. The ubiquitin proteasome system can disturb the protein homeostasis within the cell and generate a dysfunctional myocyte. The matrix metalloproteases disrupt the collagen/elastin ratio and connexins to generate arrhythmias. The concept of cardiac resuscitation stems from protecting the myocyte cytoskeleton and keeping the protein homeostasis intact through management of the degradation machinery. In this regard, proteasome inhibitors for the degradation machinery have an elegant space. Recently exosomes have been identified potentially, as carriers of microRNAs or proteins that can modify the target cells. Exosomes loaded with the inhibitor "cargo" which comprises microRNAs, siRNAs or proteins to inhibit the degradation machinery can be a method of choice for cardiac resuscitation-a process difficult to execute.

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Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE<sup>−/−</sup> mice

Cited by 33 publications

References 34 publications

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

FABP4-mediated homocysteine-induced cholesterol accumulation in THP-1 monocyte-derived macrophages and the potential epigenetic mechanism

Resuscitation of a dead cardiomyocyte

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