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Articles by M Horii
Total Records ( 4 ) for M Horii
  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.

  M Ii , H Nishimura , H Sekiguchi , N Kamei , A Yokoyama , M Horii and T. Asahara

Rationale: Recent reports have demonstrated that signals from vascular endothelial cells are necessary for organogenesis that may precede vasculogenesis. However, the origin of these neovascular cells in regenerating tissue has not been clarified.

Objective: Here we tested the hypothesis that adult neural stem cells (NSCs) can differentiate into vascular lineage, as well as neural lineage, in the process of collaborative organogenesis.

Methods and Results: NSCs, clonally isolated from mouse brain, were shown to develop endothelial and smooth muscle phenotypes in vitro. To elucidate whether NSCs can simultaneously differentiate into vascular and neural cells in vivo, genetically labeled NSCs were administered to mice with unilateral sciatic nerve crush injury or operatively induced brain and myocardial ischemia. Two weeks later, necropsy examination disclosed recruitment of the labeled NSCs to sites of injury differentiating into vascular cells (endothelial cells and vascular smooth muscle cells) and Schwann cells in regenerating nerve. Similarly, NSC-derived vascular cells/astrocytes and endothelial cells were identified in ischemic brain tissue and capillaries in myocardium 2 weeks following transplantation, respectively.

Conclusions: These findings, concurrent vasculogenesis and neurogenesis from a common stem cell, suggest that certain somatic stem cells are capable of differentiating into not only somatic cells of identity but also into vascular cells for tissue regeneration.

  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.

  T Matsumoto , M Ii , H Nishimura , T Shoji , Y Mifune , A Kawamoto , R Kuroda , T Fukui , Y Kawakami , T Kuroda , S. M Kwon , H Iwasaki , M Horii , A Yokoyama , A Oyamada , S. Y Lee , S Hayashi , M Kurosaka , S Takaki and T. Asahara

The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)–cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF–cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF–cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing.

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