Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation

Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Blood (Impact Factor: 10.45). 06/2003; 101(10):3901-7. DOI: 10.1182/blood-2002-08-2606
Source: PubMed


Although hyperhomocysteinemia is an independent risk factor for cardiovascular disease, a direct role for homocysteine (Hcy) in this disease remains to be shown. Whereas diet-induced hyperhomocysteinemia promotes atherosclerosis in animal models, the effects of Hcy on atherogenesis in the absence of dietary perturbations is not known. We have generated double knock-out mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine beta-synthase (CBS), which converts Hcy to cystathionine. ApoE(-/-)/CBS(-/-) mice developed aortic lesions even in the absence of dietary manipulation; lesion area and lesion cholesteryl ester (CE) and triglyceride (TG) contents increased with animal age and plasma Hcy levels. Plasma total cholesterol was significantly increased, whereas high density lipoprotein (HDL) cholesterol and TG concentrations of apoE(-/-)/CBS(-/-) mice were decreased. Cholesterol esterification and activities of enzymes catalyzing CE or TG formation in the vessel wall and in peritoneal macrophages were not changed by hyperhomocysteinemia. However, uptake of human acetyl-LDL, but not native low density lipoprotein (LDL), by mouse peritoneal macrophages was higher in the presence of hyperhomocysteinemia. These results suggest that isolated hyperhomocysteinemia is atherogenic and alters hepatic and macrophage lipoprotein metabolism, in part, by enhancing uptake of modified LDL.

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    • "In vertebrates, severe growth retardation and early death were observed in CBS-/- KO mice [44], and RNAi-mediated knockdown of Drosophila CBS blocked the lifespan extension associated with dietary restriction, whereas CBS overexpression markedly increased Drosophila longevity [37]. Furthermore, H2S levels and CBS enzyme activity were shown to be reduced in homocystinuria [45,46] and liver cirrhosis [47]. Collectively, our findings are in agreement with these reports and suggest a vital role of endogenous H2S and CBS-related enzymes in maintaining normal development and healthy lifespan. "
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    ABSTRACT: Exogenous hydrogen sulfide (H2S) administration and endogenous H2S metabolism were explored in the nematode C. elegans. Chronic treatment with a slow-releasing H2S donor, GYY4137, extended median survival by 17-23% and increased tolerance towards oxidative and endoplasmic reticulum (ER) stress. Also, cysl-2, a sulfhydrylase/cysteine synthase in C. elegans, was transcriptionally upregulated by GYY4137 treatment and the deletion of cysl-2 resulted in a significant reduction in lifespan which was partially recovered by the supplementation of GYY4137. Likewise, a mammalian cell culture system, GYY4137 was able to protect bovine aortic endothelial cells (BAECs) from oxidative stress and (H2O2)-induced cell death. Taken together, this provides further support that H2S exerts a protective function which is consistent with the longevity dividend theory. Overall, this study underlines the therapeutic potential of a slow-releasing H2S donor as regulators of the aging and cellular stress pathways.
    PLoS ONE 11/2013; 8(11):e80135. DOI:10.1371/journal.pone.0080135 · 3.23 Impact Factor
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    • "The results of enzymatic activities revealed significantly lower PON1 and arylesterase levels in oxytocin injected buffaloes as compared to control [14,19-21] also found a lower PON1 activity in the pregnant, early lactating and late lactating dairy cows. It might be correlated with increased level of homocysteine that triggered the atherosclerosis process due to which expression of PON1 gene in the hepatic tissue was down regulated [22,23]. It could be speculated that proatherogenic effects of tHcy might be involved in the reduction of serum PON1 activity and thus altered antioxidant function. "
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    ABSTRACT: Oxytocin has been reported for a wide range of adverse effects in different species of lactating animals. The present study was aimed to evaluate the adverse effects of oxytocin on biomarkers of oxidative stress in buffaloes. Lactating buffaloes (n = 40) were randomly selected from a commercial dairy farm located in the peri-urban area of district Faisalabad, Pakistan and divided into two equal groups viz. treatment and control groups, each containing 20 buffaloes. Buffaloes in treatment group were injected with oxytocin before each milking (morning and evening) for milk let down; whereas, animals in control group were milked naturally without oxytocin injection. Both the groups were assessed for oxidative stress biomarkers. Results showed significantly higher levels (P <= 0.05) of TOS, tHcy and ceruloplasmin oxidase activity in lactating buffaloes injected with oxytocin as compared to those of control group. On the other hand, serum levels of TAS, PON1 and arylesterase were significantly lower (P <= 0.05) in the buffaloes of treatment group. Oxytocin injection in lactating buffaloes resulted in elevated oxidative stress by increasing the total homocysteine and ceruloplasmin oxidase activity and decreasing enzymatic activities of antioxidant enzymes including paraoxonase-1 and arylesterase; that might render the animals to poor productive and reproductive potential.
    BMC Veterinary Research 08/2013; 9(1):169. DOI:10.1186/1746-6148-9-169 · 1.78 Impact Factor
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    • "The firsttier tissues may have a higher probability of experiencing acute inflammation than the second-tier and third-tier tissues. We and others showed that elevated levels of plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), is an independent risk factor, equivalent to hyperlipidemia, for cardiovascular diseases (CVD) including coronary heart disease and stroke (Maron & Loscalzo, 2009; Wang et al., 2003; Zhang et al., 2009). Recently, we performed an additional database mining study using to examine the expression of more than 20 homocysteine metabolic enzymes and methylation enzymes in >20 tissues in humans and mouse (Chen et al., 2010). "
    Bioinformatics - Trends and Methodologies, 11/2011; , ISBN: 978-953-307-282-1
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