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Articles by K Hara
Total Records ( 5 ) for K Hara
  M Kubo , K Egashira , T Inoue , J. i Koga , S Oda , L Chen , K Nakano , T Matoba , Y Kawashima , K Hara , H Tsujimoto , K Sueishi , R Tominaga and K. Sunagawa
 

Objective— Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.

Methods and Results— In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.

Conclusions— NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

  S Hamada , K Hara , T Hamada , H Yasuda , H Moriyama , R Nakayama , M Nagata and K. Yokono
  OBJECTIVE

Components of insulin/IGF-1 receptor–mediated signaling pathways in pancreatic β-cells have been implicated in the development of diabetes, in part through the regulation of β-cell mass in vivo. Studies in vitro have shown that the protein Ras homolog enriched in brain (Rheb) plays a key role as a positive upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1) pathway in integrating inputs from nutrients and growth factors for cell growth. Our objective was to investigate the role of the mTORC1 pathway in the regulation of β-cell mass in vivo.

RESEARCH DESIGN AND METHODS

We generated transgenic mice that overexpress Rheb in β-cells. We examined the activation of the mTORC1 pathway and its effects on β-cell mass, on glucose metabolism, and on protection against hyperglycemia.

RESULTS

Immunoblots of islet extracts revealed that the phosphorylation levels of ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1, downstream effectors for mTORC1, were upregulated in transgenic β-cells. Immunostaining of the pancreatic sections with anti–phospho-S6 antibody confirmed upregulation of the mTORC1 pathway in β-cells in vivo. The mice showed improved glucose tolerance with higher insulin secretion. This arose from increased β-cell mass accompanied by increased cell size. The mice also exhibited resistance to hyperglycemia induced by streptozotocin and obesity.

CONCLUSIONS

Activation of the mTORC1 pathway by Rheb led to increased β-cell mass in this mouse model without producing obvious unfavorable effects, giving a potential approach for the treatment of β-cell failure and diabetes.

  K Hara , T Yokoo , R Kajita , T Onishi , S Yahata , K. M Peterson , K. U Torii and T. Kakimoto
 

Regulation of the number of cells is critical for development of multicellular organisms. During plant epidermal development, a protodermal cell first makes a fate decision of whether or not to be the meristemoid mother cell (MMC), which undergoes asymmetric cell division forming a meristemoid and its sister cell. The MMC-derived lineage produces all stomatal guard cells and a large proportion of non-guard cells. We demonstrate that a small secretory peptide, EPIDERMAL PATTERING FACTOR 2 (EPF2), is produced by the MMC and its early descendants, and negatively regulates the density of guard and non-guard epidermal cells. Our results suggest that EPF2 inhibits cells from adopting the MMC fate in a non-cell-autonomous manner, thus limiting the number of MMCs. This feedback loop is critical for regulation of epidermal cell density. The amino acid sequence of EPF2 resembles that of EPF1, which is known to control stomatal positioning. Over-expression of EPF1 also inhibits stomatal development, but EPF1 can act only on a later developmental process than EPF2. Overexpression and promoter swapping experiments suggested that the protein functions of EPF1 and EPF2, rather than the expression patterns of the genes, are responsible for the specific functions. Although targets of EPF1 and EPF2 are different, both EPF1 and EPF2 require common putative receptor components TOO MANY MOUTHS (TMM), ERECTA (ER), ERECTA LIKE 1 (ERL1) and ERL2 in order to function.

  X Song , Y Kusakari , C. Y Xiao , S. D Kinsella , M. A Rosenberg , M Scherrer Crosbie , K Hara , A Rosenzweig and T. Matsui
 

Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-B-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.

  K Hara , T Mochizuki , I Sekiya , K Yamaguchi , K Akita and T. Muneta
  Background

Double-bundle anterior cruciate ligament (ACL) reconstruction has several potential advantages over single-bundle reconstruction with hamstring tendons. However, there are still controversies regarding tunnel placement in tibial and femoral attachments.

Hypothesis

The macroscopically normal ACL consists of small bundles about 1 mm in diameter. Detailed observation of the divided smaller bundles will achieve better understanding of the tunnel placement in anatomic ACL reconstruction.

Study Design

Descriptive laboratory study.

Methods

This study used 20 cadaveric knees. The ACL was divided into anteromedial and posterolateral bundles, then separated into 10 small bundles of 2-mm diameters, with preservation of their attachment sites marked with color markers. The positional relationship between the femoral and tibial attachments of each small bundle was investigated.

Results

A layered positional correlation of small bundles was found between the tibial and femoral attachments. Small bundles aligned in the anterior-posterior direction in the tibia corresponded to the bundles aligned in a high-low direction in the femur in flexion. The femoral attachment pattern was relatively similar in each specimen; however, the tibial attachment showed 2 patterns: an oblique type (12 of 20) and a transverse type (8 of 20). The posterior portion of the posterolateral bundle was separately attached to the medial and lateral portions of the tibial attachment. There was no fibrous insertion in the center of the posterior portion of the ACL tibial attachment in any specimen. In this bare area, there was fat tissue and vascular bundles.

Conclusion

Small bundles constituting the ACL showed a relatively layered arrangement between 2 attachments. The tibial attachment showed 2 patterns of oblique and transverse types, and the vascular bundles were located in the center of the posterolateral bundle.

Clinical Relevance

The results of this study of the normal ACL will provide insights for surgeons when placing grafts during anatomic ACL reconstruction.

 
 
 
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