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Articles by K Imagawa
Total Records ( 3 ) for K Imagawa
  Y Takemoto , H Kawata , T Soeda , K Imagawa , S Somekawa , Y Takeda , S Uemura , M Matsumoto , Y Fujimura , J. i Jo , Y Kimura , Y Tabata and Y. Saito
 

Background— In-stent thrombosis is mainly triggered by adenosine diphosphate (ADP)-dependent platelet aggregation after percutanous coronary stent implantation. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP to adenosine monophosphate, inhibiting platelet aggregation. We tested the hypothesis that local delivery of human placental E-NTPDase (pE-NTPDase) gene into injured arteries via gene-eluting stent could prevent subacute in-stent thrombosis.

Methods and Results— We generated gene-eluting stents by coating bare metal stents with cationic gelatin hydrogel containing pE-NTPDase cDNA (pE-NTPDase stent), and implanted the stents into rabbit femoral arteries (FA) prone to production of platelet-rich thrombi due to repeated balloon injury at 4-week intervals. After the second injury, E-NTPDase gene expression was severely decreased; however, the implantation of pE-NTPDase stent increased E-NTPDase mRNA levels and NTPDase activity to higher level than normal FA. The FAs with pE-NTPDase stents maintained patency in all rabbits (P<0.01), whereas the stent-implanted FAs without pE-NTPDase gene showed low patency rates (17% to 25%). The occlusive platelet-rich thrombi, excessive neointimal growth, and infiltration of macrophages were inhibited in stent implanted FA with pE-NTPDase gene, but not without pE-NTPDase gene.

Conclusions— Human pE-NTPDase gene transfer via cationic gelatin-coated stents inhibited subacute in-stent thrombosis and suppressed neointimal hyperplasia and inflammation without antiplatelet drugs.

  K Onoue , S Uemura , Y Takeda , S Somekawa , H Iwama , K Imagawa , T Nishida , Y Morikawa , Y Takemoto , O Asai , T Soeda , S Okayama , K Ishigami , K Nakatani , H Kawata , M Horii , T Nakajima , Y Akai , M Iwano and Y. Saito
 

Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure.

Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)–nephrectomized apolipoprotein E–deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6–nephrectomized apolipoprotein E–deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration.

Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

  S Somekawa , K Imagawa , N Naya , Y Takemoto , K Onoue , S Okayama , Y Takeda , H Kawata , M Horii , T Nakajima , S Uemura , N Mochizuki and Y. Saito
 

Aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) regulate aldosterone and cortisol production, respectively. The expression of these enzymes is promoted by calcium influx through Cav3.2, a T-type calcium channel. Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencer element (NRSE) to suppress the transcription of NRSE-containing genes. We found a NRSE-like sequence in human CYP11B2 and CYP11B1 genes as well as the CACNA1H gene of many mammalian species. The CACNA1H gene encodes the -subunit of Cav3.2. Here we investigated how NRSF/NRSE regulates aldosterone and cortisol synthesis. Inhibition of endogenous NRSF by an adenovirus-expressing dominant-negative NRSF (AD/dnNRSF) increased human CYP11B2 and CYP11B1 mRNA expression, leading to aldosterone and cortisol secretion in human adrenocortical (H295R) cells. In reporter gene experiments, NRSE suppressed luciferase reporters driven by CYP11B2 and CYP11B1 promoters and dnNRSF enhanced them. Moreover, cotransfection of dnNRSF increased luciferase activity of reporter genes after deletion or mutation of NRSE, suggesting that NRSF/NRSE regulates transcription of CYP11B2 and CYP11B1 genes indirectly. AD/dnNRSF augmented mRNA expression of rat CYP11B2 and CYP11B1 genes, neither of which contains a NRSE-like sequence in rat adrenal cells. AD/dnNRSE also significantly increased CACNA1H mRNA in H295R and rat adrenal cells. Efonidipine, a T/L-type calcium channel blocker, significantly suppressed dnNRSF-mediated up-regulation of CYP11B2 and CYP11B1 expression. Moreover, NRSF/NRSE is also involved in angiotensin II- and K+-stimulated augmentation of CYP11B2 and CYP11B1 gene transcription. In conclusion, NRSF/NRSE controls aldosterone and cortisol synthesis by regulating CYP11B2 and CYP11B1 gene transcription mainly through NRSF/NRSE-mediated enhancement of the CACNA1H gene.

 
 
 
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