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Articles by K. Fukuda
Total Records ( 3 ) for K. Fukuda
  T Koyama , T Mayahara , T Wakamatsu , I Sora and K. Fukuda
  Background

The role of the endogenous opioid system in the anaesthetic effect of volatile anaesthetics and the analgesic action of nitrous oxide (N2O) is unclear. In the current study, we investigated whether the µ-opioid receptor (MOP) is involved in these activities using MOP knockout (MOP-KO) and wild-type (WT) mice.

Methods

Minimum alveolar concentrations (MACs) for sevoflurane, isoflurane, and halothane, and the sevoflurane MAC-sparing effect of N2O were determined in homozygous MOP-KO and WT mice. The analgesic effect of N2O and the suppressive effect of naloxone on N2O analgesia were assessed in a writhing test and a hot-plate test. Immunohistochemical staining was used to visualize N2O-induced c-Fos expression in the lumbar spinal cord.

Results

There were no significant differences in the MAC values of the three volatile anaesthetics or in the sevoflurane MAC-sparing effect of N2O 70% between MOP-KO and WT mice. There was also no significant difference in the analgesic effect of N2O 70% or in the level of c-Fos expression induced by N2O 70% between the two genotypes. In the writhing test, naloxone significantly attenuated N2O analgesia in MOP-KO and WT mice.

Conclusions

These results suggest that MOP is not required for the anaesthetic action of volatile anaesthetics and the analgesic effect of N2O. Opioid receptors other than MOP may mediate the analgesic action of N2O.

  J Endo , M Sano , T Katayama , T Hishiki , K Shinmura , S Morizane , T Matsuhashi , Y Katsumata , Y Zhang , H Ito , Y Nagahata , S Marchitti , K Nishimaki , A. M Wolf , H Nakanishi , F Hattori , V Vasiliou , T Adachi , I Ohsawa , R Taguchi , Y Hirabayashi , S Ohta , M Suematsu , S Ogawa and K. Fukuda
 

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 2 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.

  S Yuasa , T Onizuka , K Shimoji , Y Ohno , T Kageyama , S. H Yoon , T Egashira , T Seki , H Hashimoto , T Nishiyama , R Kaneda , M Murata , F Hattori , S Makino , M Sano , S Ogawa , O. W. J Prall , R. P Harvey and K. Fukuda
 

Rationale: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors.

Objective: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor.

Methods and Results: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or MHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls.

Conclusions: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.

 
 
 
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