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Articles by Y Arai
Total Records ( 6 ) for Y Arai
  S Yasuno , S Usami , K Kuwahara , M Nakanishi , Y Arai , H Kinoshita , Y Nakagawa , M Fujiwara , M Murakami , K Ueshima , M Harada and K. Nakao
 

Ventricular myocytes are known to show increased expression of the cardiac hormones atrial and brain natriuretic peptide (ANP and BNP, respectively) in response to pathological stress on the heart, but their function during the progression of nonischemic dilated cardiomyopathy remains unclear. In this study, we crossed a mouse model of dilated cardiomyopathy and sudden death, which we generated by cardioselectively overexpressing a dominant-negative form of the transcriptional repressor neuron-restrictive silencer factor (dnNRSF Tg mice), with mice lacking guanylyl cyclase-A (GC-A), a common receptor for ANP and BNP, to assess the effects of endogenously expressed natriuretic peptides during progression of the cardiomyopathy seen in dnNRSF Tg mice. We found that dnNRSF Tg;GC-A–/– mice were born normally, but then most died within 4 wk. The survival rates among dnNRSF Tg;GC-A+/– and dnNRSF Tg mice were comparable, but dnNRSF Tg;GC-A+/– mice showed greater systolic dysfunction and a more severe cardiomyopathic phenotype than dnNRSF Tg mice. Collectively, our findings suggest that endogenous ANP/BNP protects the heart against the death and progression of pathological remodeling in a mouse model of dilated cardiomyopathy and sudden death.

  T Kubo , Y Kuroda , H Shimizu , A Kokubu , N Okada , F Hosoda , Y Arai , Y Nakamura , H Taniguchi , K Yanagihara , I Imoto , J Inazawa , S Hirohashi and T. Shibata
 

The tyrosine kinase (TK) family is an important regulator of signaling pathways that control a variety of physiological and pathological conditions, and a substantial proportion of TK genes are genetically altered in cancer. To clarify the somatic mutation profile of TK genes and discover potential targets for gastric cancer (GC) therapy, we undertook a systematic screening of mutations in the kinase domains of all human TK genes (636 exons of 90 genes) in 17 GC cell lines and 52 microdissected primary GCs with poorly differentiated histology. We identified 26 non-synonymous alterations (22 genes in total) that included 11 sequence alterations in cell lines and 15 somatic mutations in primary tumors. Recurrent mutations were found in four genes including a known oncogene (NTRK3), the Src kinase family (LTK and CSK) and a potential Wnt signal activator (ROR2). In addition, we analyzed copy number alterations of all the TK gene loci in the same cohort samples by array-based comparative genomic hybridization analysis and identified 24 high-level amplifications and two homozygous deletions. Both sequence alteration and frequent copy number aberration were detected in two TK genes (HCK and ERBB2), strongly suggesting that they encode potential oncogenes in GC. Our focused and integrated analyses of systemic resequencing and gene copy number have revealed the novel onco-kinome profile of GC and pave the way to a comprehensive understanding of the GC genome.

  H Kinoshita , K Kuwahara , M Takano , Y Arai , Y Kuwabara , S Yasuno , Y Nakagawa , M Nakanishi , M Harada , M Fujiwara , M Murakami , K Ueshima and K. Nakao
 

Background— Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca2+ channels contributes to the progression of heart failure. The ability of T-type Ca2+ channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.

Methods and Results— We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca2+ channel blockers, with those of nitrendipine, a selective L-type Ca2+ channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(–)-isomer of efonidipine, a recently identified, highly selective T-type Ca2+ channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.

Conclusions— T-type Ca2+ channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca2+ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca2+ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

 
 
 
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