Papers - Katsumata, Yoshinori

Frequent long-distance flyer's undesirable mileage

Katsumata Yoshinori, Kimura Kensuke, Sano Motoaki, Kudo Mikihiko, Arai Takahide, Ohno Yohei, Tamura Yuichi, Tsuruta Hikaru, Murata Mitsushige, Yozu Ryohei, Fukuda Keiichi

Journal of Thrombosis and Thrombolysis 33 ( 3 ) 296 - 298 2012.04

ISSN  0929-5305

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Frequent long-distance flyer's undesirable mileage

Katsumata Yoshinori, Kimura Kensuke, Sano Motoaki, Kudo Mikihiko, Arai Takahide, Ohno Yohei, Tamura Yuichi, Tsuruta Hikaru, Murata Mitsushige, Yozu Ryohei, Fukuda Keiichi

Journal of Thrombosis and Thrombolysis 33 ( 3 ) 296 - 298 2012.04

ISSN  0929-5305

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Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain

Shinmura Ken, Tamaki Kayoko, Sano Motoaki, Nakashima-Kamimura Naomi, Wolf Alexander M., Amo Taku, Ohta Shigeo, Katsumata Yoshinori, Fukuda Keiichi, Ishiwata Kyoko, Suematsu Makoto, Adachi Takeshi

Circulation Research 109 ( 4 ) 396 - 406 2011.08

ISSN  0009-7330

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<p>Rationale: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. Objective: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Methods and Results: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H2O2 production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose Resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose Resveratrol. Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.</p>

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Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain

Shinmura Ken, Tamaki Kayoko, Sano Motoaki, Nakashima-Kamimura Naomi, Wolf Alexander M., Amo Taku, Ohta Shigeo, Katsumata Yoshinori, Fukuda Keiichi, Ishiwata Kyoko, Suematsu Makoto, Adachi Takeshi

Circulation Research 109 ( 4 ) 396 - 406 2011.08

ISSN  0009-7330

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<p>Rationale: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. Objective: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Methods and Results: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H2O2 production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose Resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose Resveratrol. Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion. © 2011 American Heart Association, Inc.</p>

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4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway

Zhang Yan, Sano Motoaki, Shinmura Ken, Tamaki Kayoko, Katsumata Yoshinori, Matsuhashi Tomohiro, Morizane Shintaro, Ito Hideyuki, Hishiki Takako, Endo Jin, Zhou Heping, Yuasa Shinsuke, Kaneda Ruri, Suematsu Makoto, Fukuda Keiichi

Journal of Molecular and Cellular Cardiology 49 ( 4 ) 576 - 586 2010.10

ISSN  0022-2828

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<p>Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). There is compelling evidence that high concentrations of aldehydes are responsible for much of the damage elicited by cardiac ischemia-reperfusion injury, while sublethal concentrations of aldehydes stimulate stress resistance pathways, to achieve cardioprotection. We investigated the mechanism of cardioprotection mediated by 4-HNE. For cultured cardiomyocytes, 4-HNE was cytotoxic at higher concentrations (≥20μM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5μM) of 4-HNE primed cardiomyocytes to become resistant to cytotoxic concentrations of 4-HNE. 4-HNE induced nuclear translocation of transcription factor NF-E2-related factor 2 (Nrf2), and enhanced the expression of γ-glutamylcysteine ligase (GCL) and the core subunit of the Xc^- high-affinity cystine transporter (xCT), thereby increasing 1.45-fold the intracellular GSH levels. Cardiomyocytes treated with either Nrf2-specific siRNA or the GCL inhibitor l-buthionine sulfoximine (BSO) were less tolerant to 4-HNE. Moreover, the cardioprotective effect of 4-HNE pretreatment against subsequent glucose-free anoxia followed by reoxygenation was completely abolished in these cells. Intravenous administration of 4-HNE (4mg/kg) activated Nrf2 in the heart and increased the intramyocardial GSH content, and consequently improved the functional recovery of the left ventricle following ischemia-reperfusion in Langendorff-perfused hearts. This cardioprotective effect of 4-HNE was not observed for Nrf2-knockout mice. In summary, 4-HNE activates Nrf2-mediated gene expression and stimulates GSH biosynthesis, thereby conferring on cardiomyocytes protection against ischemia-reperfusion injury.</p>

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Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart

Endo Jin, Sano Motoaki, Katayama Takaharu, Hishiki Takako, Shinmura Ken, Morizane Shintaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Zhang Yan, Ito Hideyuki, Nagahata Yoshiko, Marchitti Satori, Nishimaki Kiyomi, Wolf Alexander Martin, Nakanishi Hiroki, Hattori Fumiyuki, Vasiliou Vasilis, Adachi Takeshi, Ohsawa Ikuroh, Taguchi Ryo, Hirabayashi Yoshio, Ohta Shigeo, Suematsu Makoto, Ogawa Satoshi, Fukuda Keiichi

Circulation Research 105 ( 11 ) 1118 - 1127 2009.11

ISSN  0009-7330

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<p>RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.</p>

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