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Articles by Y Nakagawa
Total Records ( 11 ) for Y Nakagawa
  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.

  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.

  K Yamaji , T Kimura , T Morimoto , Y Nakagawa , K Inoue , Y Soga , T Arita , S Shirai , K Ando , K Kondo , K Sakai , M Goya , M Iwabuchi , H Yokoi , H Nosaka and M. Nobuyoshi
  Background—

We previously reported that the long-term luminal response after coronary bare metal stenting is triphasic, with an early restenosis phase spanning the 6 months after the index procedure, an intermediate-term regression phase from 6 months to 3 years, and a late renarrowing phase beyond 4 years. However, the clinical significance of late luminal renarrowing remains unknown.

Methods and Results—

Angiographic and clinical follow-up of the same cohort of 405 patients with successful Palmaz-Schatz stent placement was extended beyond 15 years. Clinical follow-up was completed in 98% of patients at 5 years and in 81% at 15 years. The incidence of death and cardiac death at 15 years was 45.4% and 20.6%, respectively. Paired long-term (4 to 10 years) and very long-term (>10 years) angiographic studies without intercurrent target lesion revascularization were performed in 55 lesions, and minimal luminal diameter further decreased from 1.88±0.50 mm to 1.60±0.73 mm (P=0.002). Late target lesion revascularization after initial stabilization of the stented segments occurred rarely within 4 years. Beyond 4 years, however, the incidence of late target lesion revascularization increased steadily from 3.3% at 4 years to 24.7% at 15 years. The incidence of definite very late stent thrombosis was low (1.5% at 15 years).

Conclusions—

Luminal renarrowing of the stented segment beyond 4 years was a progressive process extending beyond 10 years. The angiographic observation of late in-stent restenosis was clinically relevant because a corresponding progressive increase in the incidence of late target lesion revascularization was observed beyond 4 years and up to 15 to 20 years after bare metal stent implantation.

  B Cubero , Y Nakagawa , X. Y Jiang , K. J Miura , F Li , K. G Raghothama , R. A Bressan , P. M Hasegawa and J. M. Pardo
 

Insertion mutations that disrupt the function of PHT4;6 (At5g44370) cause NaCl hypersensitivity of Arabidopsis seedlings that is characterized by reduced growth of the primary root, enhanced lateral branching, and swelling of root tips. Mutant phenotypes were exacerbated by sucrose, but not by equiosmolar concentrations of mannitol, and attenuated by low inorganic phosphate in the medium. Protein PHT4;6 belongs to the Major Facilitator Superfamily of permeases that shares significant sequence similarity to mammalian type-I Pi transporters and vesicular glutamate transporters, and is a member of the PHT4 family of putative intracellular phosphate transporters of plants. PHT4;6 localizes to the Golgi membrane and transport studies indicate that PHT4;6 facilitates the selective transport of Pi but not of chloride or inorganic anions. Phenotypic similarities with other mutants displaying root swelling suggest that PHT4;6 likely functions in protein N-glycosylation and cell wall biosynthesis, which are essential for salt tolerance. Together, our results indicate that PHT4;6 transports Pi out of the Golgi lumenal space for the re-cycling of the Pi released from glycosylation processes.

  H Shimizu , Y Nakagawa , C Murakami , N Aoki , S Kim Mitsuyama and H. Miyazaki
 

Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase M (PTPM) promotes VEC survival and migration. The present study investigates the biological functions of PTPM in VSMCs and determines whether PTPM is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTPM and an small interfering RNA (siRNA) of PTPM by using an adenovirus vector to investigate the effects of PTPM upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTPM decreased PDGF-induced DNA synthesis and migration by reducing the phosphorylation level of the PDGF β-receptor (PDGFRβ) with subsequently suppressed H2O2 generation. The HG content in the medium generated H2O2, upregulated PDGFRβ expression and its tyrosine-phosphorylation, and elevated NADPH oxidase 1 (Nox1) expression even without exogenous PDGF, all of which were downregulated by PTPM. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and H2O2 production. Moreover, HG suppressed PTPM expression itself, which was blocked by the antioxidant N-acetyl-l-cysteine. The effects of PTPM siRNA were the opposite of those of wild-type PTPM. Therefore, PTPM negatively regulates PDGFRβ-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTPM may be involved in diabetes-accelerated atherosclerosis.

  K Nishiyama , M Horiguchi , S Shizuta , T Doi , N Ehara , R Tanuguchi , Y Haruna , Y Nakagawa , Y Furukawa , M Fukushima , T Kita and T. Kimura
  Background

The incidence of strokes has not decreased after coronary artery bypass graft surgery (CABG). The purpose of this study is to identify incidence, risk factors, and temporal pattern of strokes after on-pump and off-pump CABG.

Methods

We analyzed 2,516 consecutive patients who underwent first elective isolated CABG. The primary endpoint was strokes within 30 days. The temporal onset of the deficits was classified by consensus as either an "early stroke," which is present just after emergence from anesthesia, or a "delayed stroke," which is present after first awaking from surgery without a neurologic deficit.

Results

More than half of strokes (29 of 46; 63%) were delayed strokes. Patients undergoing off-pump CABG had significantly lower risk of early stroke (0.1% versus 1.1%, p = 0.0009), whereas the incidence of delayed strokes was not different significantly (0.9% versus 1.4%, p = 0.3484) between patients undergoing on-pump and off-pump CABG. In multivariate analyses, undergoing off-pump CABG was an independent protective factor for all strokes (relative risk 0.29, 95% confidence interval: 0.14 to 0.56, p = 0.0005) and early strokes (relative risk 0.05, 95% confidence interval: 0.003 to 0.24, p < 0.0001), but it was not an independent protective factor for delayed strokes (relative risk 0.54, 95% confidence interval: 0.24 to 1.17, p = 0.1210).

Conclusions

Undergoing off-pump CABG reduces the incidence of perioperative stroke mainly by minimizing early strokes; however, the risk of delayed strokes is not different between patients undergoing on-pump and off-pump CABG.

  M Suzuki , A Niimi , S Limsirichaikul , S Tomida , Q Miao Huang , S Izuta , J Usukura , Y Itoh , T Hishida , T Akashi , Y Nakagawa , A Kikuchi , Y Pavlov , T Murate and T. Takahashi
 

Translesion DNA synthesis (TLS) involves PCNA mono-ubiquitination and TLS DNA polymerases (pols). Recent evidence has shown that the mono-ubiquitination is induced not only by DNA damage but also by other factors that induce stalling of the DNA replication fork. We studied the effect of spontaneous DNA replication errors on PCNA mono-ubiquitination and TLS induction. In the pol1L868F strain, which expressed an error-prone pol , PCNA was spontaneously mono-ubiquitinated. Pol L868F had a rate-limiting step at the extension from mismatched primer termini. Electron microscopic observation showed the accumulation of a single-stranded region at the DNA replication fork in yeast cells. For pol errors, pol participated in a generation of +1 frameshifts. Furthermore, in the pol1L868F strain, UV-induced mutations were lower than in the wild-type and a pol mutant strain (pol3-5DV), and deletion of the RAD30 gene (pol ) suppressed this defect. These data suggest that nucleotide misincorporation by pol induces exposure of single-stranded DNA, PCNA mono-ubiquitination and activates TLS pols.

  H Nakao , I Matsunaga , D Morita , T Aboshi , T Harada , Y Nakagawa , N Mori and M. Sugita
 

Trehalose dimycolate (TDM) is a major surface-exposed mycolyl glycolipid that contributes to the hydrophobic cell wall architecture of mycobacteria. Nevertheless, because of its potent adjuvant functions, pathogenic mycobacteria appear to have evolved an evasive maneuver to down-regulate TDM expression within the host. We have shown previously that Mycobacterium tuberculosis (M.tb) and Mycobacterium avium (M.av), replace TDM with glucose monomycolate (GMM) by borrowing host-derived glucose as an alternative substrate for the FbpA mycolyltransferase. Mycobacterium leprae (M.le), the causative microorganism of human leprosy, is also known to down-regulate TDM expression in infected tissues, but the function of its mycolyltransferases has been poorly analysed. We found that, unlike M.tb and M.av FbpA enzymes, M.av FbpA was unexpectedly inefficient in transferring -branched mycolates, resulting in impaired production of both TDM and GMM. Molecular modelling and mutational analysis indicated that a bulky side chain of leucine at position 130 of M.le FbpA obstructed the intramolecular tunnel that was proposed to accommodate the -branch portion of the substrates. Notably, even after a highly reductive evolution, M.le FbpA remained functional in terms of transferring unbranched acyl chains, suggesting a role that is distinct from that as a mycolyltransferase.

 
 
 
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