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Papers - ITOH Hiroshi

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Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats

Takimoto, C., Kumagai, H., Osaka, M., Sakata, K., Onami, T., Kamayachi, T., Iigaya, K., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 ( 10 ) 1941 - 51 2008.10

ISSN 0916-9636

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

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Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice

Oyamada, N., Itoh, H., Sone, M., Yamahara, K., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

J Transl Med 6 54 2008.09

ISSN 1479-5876

BACKGROUND: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain. METHODS: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo). RESULTS: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice. CONCLUSION: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

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Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Nishiyama, A. and Itoh, H.

J Am Soc Hypertens 2 ( 5 ) 332 - 40 2008.09

ISSN 1933-1711

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.

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The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia

Oyamada, N., Sone, M., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N., Itoh, H. and Nakao, K.

Endocrinology 149 ( 8 ) 3764 - 77 2008.08

ISSN 0013-7227

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.

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Monosynaptic excitatory connection from the rostral ventrolateral medulla to sympathetic preganglionic neurons revealed by simultaneous recordings

Oshima, N., Kumagai, H., Onimaru, H., Kawai, A., Pilowsky, P. M., Iigaya, K., Takimoto, C., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 ( 7 ) 1445 - 54 2008.07

ISSN 0916-9636

To directly investigate whether a monosynaptic connection exists between neurons in the rostral ventrolateral medulla (RVLM) and sympathetic preganglionic neurons (SPNs), we used simultaneous extracellular recordings of RVLM neurons and whole-cell patch-clamp recordings of SPNs at the Th2 level and analyzed them by spike-triggered averaging. We averaged 200 sweeps of membrane potentials in SPN triggered by the spikes in the RVLM neuron. No clear postsynaptic potentials were detected in the averaged wave of SPNs before angiotensin II (Ang II) superfusion, whereas during superfusion with Ang II (6 micromol/L) on the medulla oblongata side alone excitatory postsynaptic potentials (EPSPs) were clearly found in the SPN of 3 out of 10 pairs at 40 +/- 1 ms after the averaged triggering spike in the RVLM neuron. We consider them to be monosynaptic EPSPs, because 1) the averaged EPSPs exhibited a sharp rise time, 2) the onset latency of the averaged EPSPs in the SPNs after the trigger spike in the RVLM was the same as the latency of the antidromic action potentials in the RVLM neurons in response to electrical stimulation of the SPNs, and 3) the amplitude of the averaged EPSPs was over 2 mV. In summary, combining simultaneous recording and spike-triggered averaging allowed us to demonstrate a monosynaptic excitatory connection between a single RVLM neuron and a single SPN in the thoracic spinal cord. Such connections provide the basis for the maintenance of sympathetic tone and the integrative reflex that relays through the RVLM. The results explain the mechanism by which Ang II in the RVLM area increases peripheral sympathetic activity and blood pressure.

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Pathologic roles of prorenin and (pro)renin receptor in the eye

Satofuka, S., Ichihara, A., Nagai, N., Tsubota, K., Itoh, H. and Ishida, S.

Front Biosci 13 3884 - 95 2008.05

ISSN 1093-9946

Recent reports indicated that tissue renin-angiotensin system (RAS) was upregulated and angiotensin II type 1 receptor signaling plays crucial roles in ocular inflammation and neovascularization; however, the precise mechanism for activating tissue RAS had not been defined until recently. (Pro)renin receptor, a recently identified molecule existing in the major organs but not in the circulation, has attracted growing attention as an activator of tissue RAS. When the handle region of the prorenin prosegment binds to (pro)renin receptor, prorenin undergoes a conformational change to its enzymatically active state without the conventional proteolysis of the prorenin prosegment. Systemic treatment with a peptide with the structure of the handle region (handle region peptide; HRP), which competitively binds to (pro)renin receptor as a decoy peptide and inhibit the nonproteolytic activation of prorenin, resulted in the suppression of retinal inflammation and neovascularizaion in the rodent models. Retinal expression of RAS-related inflammatory and angiogenic molecules, such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, and vascular endothelial growth factor, was also suppressed with application of HRP. These findings demonstrate that nonproteolytically activated prorenin plays a significant role in the ocular inflammation and neovascularization.

Augmentation of neovascularization [corrected] in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells

Yamahara, K., Sone, M., Itoh, H., Yamashita, J. K., Yurugi-Kobayashi, T., Homma, K., Chao, T. H., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Fukunaga, Y., Tamura, N. and Nakao, K.

PLoS One 3 ( 2 ) e1666 2008.02

ISSN 1932-6203

BACKGROUND: We demonstrated that mouse embryonic stem (ES) cells-derived vascular endothelial growth factor receptor-2 (VEGF-R2) positive cells could differentiate into both endothelial cells (EC) and mural cells (MC), and termed them as vascular progenitor cells (VPC). Recently, we have established a method to expand monkey and human ES cells-derived VPC with the proper differentiation stage in a large quantity. Here we investigated the therapeutic potential of human VPC-derived EC and MC for vascular regeneration. METHODS AND RESULTS: After the expansion of human VPC-derived vascular cells, we transplanted these cells to nude mice with hindlimb ischemia. The blood flow recovery and capillary density in ischemic hindlimbs were significantly improved in human VPC-derived EC-transplanted mice, compared to human peripheral and umbilical cord blood-derived endothelial progenitor cells (pEPC and uEPC) transplanted mice. The combined transplantation of human VPC-derived EC and MC synergistically improved blood flow of ischemic hindlimbs remarkably, compared to the single cell transplantations. Transplanted VPC-derived vascular cells were effectively incorporated into host circulating vessels as EC and MC to maintain long-term vascular integrity. CONCLUSIONS: Our findings suggest that the combined transplantation of human ES cells-derived EC and MC can be used as a new promising strategy for therapeutic vascular regeneration in patients with tissue ischemia.

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Therapeutic potential of atrial natriuretic peptide administration on peripheral arterial diseases

Park, K., Itoh, H., Yamahara, K., Sone, M., Miyashita, K., Oyamada, N., Sawada, N., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

Endocrinology 149 ( 2 ) 483 - 91 2008.02

ISSN 0013-7227

Peripheral arterial diseases are caused by arterial sclerosis and impaired collateral vessel formation, which are exacerbated by diabetes, often leading to leg amputation. We have reported that an activation of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway accelerated vascular regeneration and blood flow recovery in murine legs, for which ischemia had been induced by a femoral arterial ligation as a model for peripheral arterial diseases. In this study, ip injection of carperitide, a human recombinant atrial natriuretic peptide, accelerated blood flow recovery with increasing capillary density in ischemic legs not only in nondiabetic mice but also in mice kept upon streptozotocin-induced hyperglycemia for 16 wk, which significantly impaired the blood flow recovery compared with nondiabetic mice. Based on these findings, we tried to apply the administration of carperitide to the treatment of peripheral arterial diseases. The study group comprised a continuous series of 13 patients with peripheral arterial diseases (Fontaine's classification I, one; II, five; III, two; and IV, five), for whom conventional therapies had not accomplished appreciable results. Carperitide was administrated continuously and intravenously for 2 wk to Fontaine's class I-III patients and for 4 weeks to class IV patients. The dose was gradually increased to the maximum, with the patient's systolic blood pressure being kept above 100 mm Hg. Carperitide administration improved the ankle-brachial pressure index, intermittent claudication, rest pain, and ulcers. In conclusion, this study showed a therapeutic potential of carperitide to treat peripheral arterial diseases refractory to conventional therapies.

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Effects of pretreatment with low-dose metformin on metabolic parameters and weight gain by pioglitazone in Japanese patients with type 2 diabetes

Kawai, T., Funae, O., Shimada, A., Tabata, M., Hirata, T., Atsumi, Y. and Itoh, H.

Intern Med 47 ( 13 ) 1181 - 8 2008

ISSN 0918-2918

OBJECTIVE: We investigated whether or not "low dose" metformin could prevent weight gain induced by pioglitazone. RESEARCH DESIGN AND METHODS: Sixty-nine patients with type 2 diabetes received 500-750 mg metformin a day for 12 weeks as an observation period before the start of the intervention. After an observation period, inadequately controlled patients (hemoglobin A1c >or=7.5%, n=34) received additional treatment with 15 mg pioglitazone (+P, M+P group). The other patients (n= 35) continued metformin monotherapy (Met group). In addition, another group consisting of 28 patients treated with 15 mg pioglitazone alone (Pio group) was observed. Body mass index (BMI), as well as several clinical parameters of glycemic control and lipid metabolism, was compared before and after 24 weeks of intervention. RESULTS: BMI increased significantly in the Pio group [24.0+/-3.8 vs. 24.8+/-4.3 kg/m(2), (mean +/- SD), p<0.001], but not in the M+P group (25.1+/-3.5 vs. 25.3+/-3.4 kg/m(2), NS) and Met group (24.0+/-3.3 vs. 24.0+/-3.5 kg/m(2), NS). In addition to improvement in glycemic control, a significant reduction in the atherogenic index of plasma (AIP), defined as log [TG x0.0112/HDL-C x0.02586], was observed in the Pio group (0.06+/-0.23 vs. -0.04+/-0.27, p<0.05) and M+P group (0.08+/-0.24 vs. -0.001+/-0.252, p<0.01), but not in the Met group. CONCLUSION: This study indicates potential benefits of the addition of pioglitazone to "low dose" metformin in terms of improvement of glucose and lipid metabolism without weight gain.

Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration

Sone, M., Itoh, H., Yamahara, K., Yamashita, J. K., Yurugi-Kobayashi, T., Nonoguchi, A., Suzuki, Y., Chao, T. H., Sawada, N., Fukunaga, Y., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Tamura, N., Kondo, Y., Nito, S., Suemori, H., Nakatsuji, N., Nishikawa, S. and Nakao, K.

Arterioscler Thromb Vasc Biol 27 ( 10 ) 2127 - 34 2007.10

ISSN 1079-5642

OBJECTIVE: We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration. METHODS AND RESULTS: Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60-negative cells were also positive for platelet-derived growth factor receptor alpha and beta chains and could be effectively differentiated into both VE-cadherin+ endothelial cell and alpha-smooth muscle actin+ mural cell. VE-cadherin+ cells, which were also CD34+ and VEGF-R2+ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow. CONCLUSIONS: We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

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心血管事故の元、動脈硬化は食い止められるか

Itoh Hiroshi

まいんど 19 ( 8月 ) 39702 2007.08

Research paper (scientific journal), Single Work

Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie, Dimethylaminohydrolase 2

Kazuhiro Hasegawa, Shu Wakino, Satoru Tatematsu, Kyoko Yoshioka, Koichiro Homma, Naoki Sugano, Masumi Kimoto, Koichi Hayashi, Itoh Hiroshi

Circulation Research e2-e10 2007.07