Yutaka Ohta

Oxidative Stress Causes Heart Failure with Impaired Mitochondrial Respiration

Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document}), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{\bar{{\cdot}}}}\) \end{document} generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.

Dose-dependent hypocholesterolemic actions of dietary apple polyphenol in rats fed cholesterol.

The dose-dependent hypocholesterolemic and antiatherogenic effects of dietary apple polyphenol (AP) from unripe apple, which contains approximately 85% catechin oligomers (procyanidins), were examined in male Sprague-Dawley rats (4 wk of age) given a purified diet containing 0.5% cholesterol. Dietary AP at 0.5 and 1.0% levels significantly decreased the liver cholesterol level compared with that in the control (AP-free dietfed) group. Dietary AP also significantly lowered the serum cholesterol level compared with that in the control group. However, the HDL cholesterol level was significantly higher in the 1.0% AP fed group than in the control group. Accordingly, the ratio of HDL-cholesterol/total cholesterol was significantly higher in the 0.5% AP-fed group and 1.0% AP-fed group than in the control group. Moreover, the atherogenic indices in the 0.5 and 1.0% AP-fed groups were significantly lower than those in the control group. The activity of hepatic cholesterol 7α-hydroxylase tended to be increased by dietary AP in a dose-dependent manner. In accord with this observation, dietary AP increased the excretion of acidic steroids in feces. Dietary AP also significantly promoted the fecal excretion of neutral steroids in a dose-dependent manner. These observations suggest that dietary AP at 0.5 or 1.0% level exerts hypocholesterolemic and antiatherogenic effects through the promotion of cholesterol catabolism and inhibition of intestinal absorption of cholesterol.

Mild caloric restriction up-regulates the expression of prohibitin: a proteome study.

Caloric restriction (CR) is well known to expand lifespan in a variety of species and to retard many age-related diseases. The effects of relatively mild CR on the proteome profile in relation to lifespan have not yet been reported, despite the more extensive studies of the stricter CR conditions. Thus, the present study was conducted to elucidate the protein profiles in rat livers after mild CR for a relatively short time. Young growing rats were fed CR diets (10% and 30% CR) for 1month. We performed the differential proteomic analysis of the rat livers using two-dimensional electrophoresis combined with MALDI-TOF mass spectrometry. The most remarkable protein among the differentially expressed proteins was found to be prohibitin, the abundance of which was increased by 30% CR. Prohibitin is a ubiquitously expressed protein shown to suppress cell proliferation and to be related to longevity. The increase in prohibitin was observed both in 10% and 30% CR by Western blot analysis. Furthermore, induction of AMP-activated kinase (AMPK) protein, related to the actions of prohibitin in promoting longevity, was observed. The increased prohibitin level in response to subtle CR suggests that this increase may be one of the early events leading to the expansion of lifespan in response to CR.

Effect of mild restriction of food intake on gene expression profile in the liver of young rats: reference data for in vivo nutrigenomics study

Recent transcriptomics studies on the effect of long-term or severe energy restriction (ER) have revealed that many genes are dynamically modulated by this condition in rodents. The present study was conducted to define the global gene expression profile in response to mild ER treatment. Growing rats were fed with reduced amount of diet (5-30 % ER) for 1 week or 1 month. Using DNA microarray analysis of the liver, seventy-two genes that were consistently changed through the different ER levels were identified. Many were related to lipid metabolism including genes encoding key enzymes such as carnitine palmitoyltransferase 1 and fatty acid synthase. Interestingly, a number of genes were altered even by 5 % ER for 1 week where no differences in weight gain were observed. The information obtained in the present study can be used as a valuable reference data source in the transcriptomics studies of food and nutrition in which subtle differences in food intake sometimes hinder appropriate interpretation of the data.

Hypocholesterolemic Effect of Dietary Apple Polyphenol Is Associated with Alterations in Hepatic Gene Expression Related to Cholesterol Metabolism in Rats

Apple polyphenol (AP) mainly consists of procyanidins and has been reported to improve blood cholesterol levels and promote excretion of cholesterol in rats fed high-cholesterol diets. To understand the molecular mechanisms underlying the effects of AP, we investigated whether dietary AP changed the hepatic expression of genes related to cholesterol metabolism and steroid transport. Four-week-old male Sprague-Dawley rats were pair-fed with diets containing 0.5% cholesterol together with 0% (control), 0.2%, and 0.5% AP, respectively, for 30 days. Administration of 0.5% AP was found to improve serum total cholesterol levels (0.69fold vs. control, p < 0.05), and increase hepatic LDL receptor (LDLR) mRNA (1.59-fold vs. control, p < 0.0001). There was a negative correlation between serum non-HDL cholesterol and LDLR mRNA (p < 0.001). Administration of 0.5% AP increased excretion of primary bile acids (2.96-fold vs. control, p < 0.0001) and up-regulated the expression of steroid catabolism genes such as sterol 12αhydroxylase (CYP8B1). However, improvements in cholesterol levels were not associated with the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. Expression of farnesoid X receptor (FXR), which is involved in the regulation of bile acid biosynthesis, was up-regulated by 0.5% AP (1.56-fold vs. control, p < 0.01), and FXR mRNA levels correlated positively with bile acid excretion (p < 0.01). These results show that dietary AP improved blood cholesterol levels with adequate intake of LDL from blood by increasing hepatic LDLR expression and promoting production of bile acid with an upregulation of genes related to steroid catabolism. KeywordsApple Polyphenol; Procyanidin; Cholesterol Metabolism; LDL Receptor