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Articles by K Ishikawa
Total Records ( 4 ) for K Ishikawa
  Y Ikeda , K. i Aihara , S Yoshida , T Sato , S Yagi , T Iwase , Y Sumitomo , T Ise , K Ishikawa , H Azuma , M Akaike , S Kato and T. Matsumoto
 

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system’s involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg · d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-β1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-β-phosphorylated Smad pathway.

  Y Ikeda , K. i Aihara , M Akaike , T Sato , K Ishikawa , T Ise , S Yagi , T Iwase , Y Ueda , S Yoshida , H Azuma , K Walsh , T Tamaki , S Kato and T. Matsumoto
 

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.

  T Nakamura , Y Kado , T Yamaguchi , H Matsumura , K Ishikawa and T. Inoue
 

Peroxiredoxin (Prx) reduces hydrogen peroxide and alkyl peroxides to water and corresponding alcohols, respectively. The reaction is dependent on a peroxidatic cysteine, whose sulphur atom nucleophilically attacks one of the oxygen atoms of the peroxide substrate. In spite of the many structural studies that have been carried out on this reaction, the tertiary structure of the hydrogen peroxide-bound form of Prx has not been elucidated. In this paper, we report the crystal structure of Prx from Aeropyrum pernix K1 in the peroxide-bound form. The conformation of the polypeptide chain is the same as that in the reduced apo-form. The hydrogen peroxide molecule is in close contact with the peroxidatic Cys50 and the neighbouring Thr47 and Arg126 side chain atoms, as well as with the main chain nitrogen atoms of Val49 and Cys50. Bound peroxide was also observed in the mutant C50S, in which the peroxidatic cysteine was replaced by serine. Therefore, the sulphur atom of the peroxidatic cysteine is not essential for peroxide binding, although it enhances the binding affinity. Hydrogen peroxide binds to the protein so that it fills the active site pocket. This study provides insight into the early stage of the Prx reaction.

  F Han , K Takeda , M Ono , F Date , K Ishikawa , S Yokoyama , Y Shinozawa , K Furuyama and S. Shibahara
 

Heme oxygenase (HO) catalyzes oxidative breakdown of heme, and constitutes two isozymes, HO-1 and HO-2. Here, we explored the tissue-specific regulation of expression of HO-1 and HO-2 under hypoxemia. There was no significant change in the overall expression levels of HO-1 and HO-2 mRNAs and proteins in the lung during adaptation of C57BL/6 mice to normobaric hypoxia (10% O2). However, immunohistochemical analysis revealed the increased expression of HO-1 and HO-2 proteins after 28 days of normobaric hypoxia in the pulmonary venous myocardium that is the extension of the left atrial myocardium into pulmonary venous walls. Moreover, the expression of HO-2 protein was increased in the sub-endocardial myocardium of ventricles under hypoxia, while HO-1 protein level was increased in the full-thickness walls. Thus, hypoxemia induces expression of both HO-1 and HO-2 proteins in the myocardium. Using C57BL/6 mice lacking HO-2 (HO-2–/–), which manifest chronic hypoxemia, we also showed that the HO-1 protein level in the lung was similar between HO-2–/– mice and wild-type mice. Unexpectedly, HO-1 protein level was lower by 35% in the HO-2–/– mouse liver than the wild-type liver. These results indicate that the expression of HO-1 protein is regulated in a tissue-specific manner under hypoxemia.

 
 
 
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