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Papers - ITOH Hiroshi

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[What is 'metabolic domino effect'?--new concept in lifestyle-related diseases]

Itoh, H.

Nihon Rinsho 61 ( 10 ) 1837 - 43 2003.10

ISSN 0047-1852

Lifestyle-related diseases such as hypertension, hyperlipidemia, and impaired glucose tolerance are independent risk factors for cardiovascular diseases. When these risk factors accumulate, the risk of cardiovascular diseases remarkably increases. This condition, marked by an accumulation of these risk factors in one person, is considered a disease entity by itself called the 'metabolic syndrome'. The effects of this syndrome over time are now being referred to as 'metabolic domino effect'. This new concept considers factors such as the flow of time and the chain reaction of the risk factors. When these risk factors accumulate in one person over time, the risk factors interact and multiply the cardiovascular risk, leading to a process similar to falling dominoes; once the process begins, it leads to cardiovascular diseases that are irreversible. Data strongly suggests that angiotensin II is a contributing factor at every step of the process in this metabolic domino effect, starting from obesity to the progression of macroangiopathy and microangiopathy. The key to effectively preventing cardiovascular diseases is to suppress production of angiotensin II at an early stage of the metabolic syndrome.

Successful treatment of primary aldosteronism due to computed tomography-negative microadenoma

Nishizawa, K., Nakamura, E., Kobayashi, T., Kamoto, T., Terai, A., Terachi, T., Ogawa, O., Itoh, H. and Nakao, K.

Int J Urol 10 ( 10 ) 544 - 6 2003.10

ISSN 0919-8172

We report a case of aldosterone-producing microadenoma that was correctly diagnosed and thus treated less invasively by laparoscopic adrenalectomy. A 58-year-old woman presented with palpitation and muscular weakness. She exhibited hypertension, hypokalemia and increased aldosterone excretion with suppressed renin activity. Therefore, primary aldosteronism was suggested. Although adrenal scintigram and computed tomography findings in the adrenal glands were normal, adrenal venous sampling tests indicated an overproduction of aldosterone in the right adrenal gland. We diagnosed an aldosterone-producing microadenoma in the right adrenal gland and performed an adrenalectomy. The patient became normotensive postoperatively and histopathological examination demonstrated a microadenoma, 5 mm in diameter.

[Significance of renin-angiotensin system in diabetes mellitus with hypertension]

Itoh, H.

Nihon Rinsho 61 ( 7 ) 1145 - 53 2003.07

ISSN 0047-1852

Diabetes mellitus and hypertension frequently occur in the same individual, based upon 'insulin resistance', which is caused by obesity and impairment of secretion of several adipocyte-derived hormones(adipocytokines), including leptin and adiponectin. Insulin resistance and activation of tissue renin-angiotensin system mutually affect each other to promote diabetes mellitus/hypertension and their complications. Especially, renin-angiotensin system in the adipose tissue modulate adipocyte differentiation and adipose tissue mass. Vascular renin-angiotensin system causes endothelial dysfunction and promotes inflammatory process to accelerate atherosclerosis. Blockade of renin-angiotensin system is reasonable for prevention and suppression of diabetes mellitus/hypertension and their complications.

Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy

Chun, T. H., Itoh, H., Subramanian, L., Iniguez-Lluhi, J. A. and Nakao, K.

Circ Res 92 ( 11 ) 1201 - 8 2003.06

ISSN 0009-7330

GATA sequences are required for the optimal expression of endothelial cell-specific genes, including endothelin-1 (ET-1). We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2-mediated endothelial gene expression. Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors. We show that GATA-2 is covalently modified by small ubiquitin-like modifier (SUMO)-1 and -2 and that PIASy, through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO-2 to GATA-2. Through a functional analysis, we demonstrate that PIASy potently suppresses the activity of the GATA-2-dependent human ET-1 promoter in endothelial cells. The suppressive effect of PIASy requires the GATA-binding site in the ET-1 promoter and depends on its interaction with GATA-2, which requires both N-terminal (amino acids 1-183) and C-terminal (amino acids 414-510) sequences in PIASy. We conclude that PIASy enhances the conjugation of SUMO-2 to GATA-2 and that the interaction of PIASy with GATA-2 can modulate GATA-mediated ET-1 transcription activity in endothelial cells through a RING-like domain-independent mechanism.

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Adrenomedullin provokes endothelial Akt activation and promotes vascular regeneration both in vitro and in vivo

Miyashita, K., Itoh, H., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi-Kobayashi, T., Park, K. and Nakao, K.

FEBS Lett 544 ( 1-3 ) 86 - 92 2003.06

ISSN 0014-5793

We previously reported that adrenomedullin (AM), a vasodilating hormone secreted from blood vessels, promotes proliferation and migration of human umbilical vein endothelial cells (HUVECs). In this study, we examined the ability of AM to promote vascular regeneration. AM increased the phosphorylation of Akt in HUVECs and the effect was inhibited by the AM antagonists and the inhibitors for protein kinase A (PKA) or phosphatidylinositol 3-kinase (PI3K). AM promoted re-endothelialization in vitro of wounded monolayer of HUVECs and neo-vascularization in vivo in murine gel plugs. These effects were also inhibited by the AM antagonists and the inhibitors for PKA or PI3K. The findings suggest that AM plays significant roles in vascular regeneration, associated with PKA- and PI3K-dependent activation of Akt in endothelial cells, and possesses therapeutic potential for vascular injury and tissue ischemia.

Different differentiation kinetics of vascular progenitor cells in primate and mouse embryonic stem cells

Sone, M., Itoh, H., Yamashita, J., Yurugi-Kobayashi, T., Suzuki, Y., Kondo, Y., Nonoguchi, A., Sawada, N., Yamahara, K., Miyashita, K., Park, K., Shibuya, M., Nito, S., Nishikawa, S. and Nakao, K.

Circulation 107 ( 16 ) 2085 - 8 2003.04

ISSN 0009-7322

BACKGROUND: We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells. METHODS AND RESULTS: In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2-positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2+ VEcadherin- cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50 ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1+ cells surrounded by SMA+ cells. In addition, these differentiated VEGF-R2+ cells can form tube-like structures in a 3-dimensional culture. CONCLUSIONS: Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2+ VEcadherin- cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.

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Effective contribution of transplanted vascular progenitor cells derived from embryonic stem cells to adult neovascularization in proper differentiation stage

Yurugi-Kobayashi, T., Itoh, H., Yamashita, J., Yamahara, K., Hirai, H., Kobayashi, T., Ogawa, M., Nishikawa, S., Nishikawa, S. and Nakao, K.

Blood 101 ( 7 ) 2675 - 8 2003.04

ISSN 0006-4971

We demonstrated that Flk-1(+) cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) to suffice as vascular progenitor cells (VPCs). In the present study, we investigated the importance of the stage of ES cell differentiation on effective participation in adult neovascularization. We obtained Flk-1(+) LacZ-expressing undifferentiated VPCs. Additional culture of these VPCs with vascular endothelial growth factor (VEGF) resulted in a mixture of ECs and MCs (differentiated VPCs). We injected VPCs subcutaneously into tumor-bearing mice. Five days after the injection, whereas undifferentiated VPCs were often detected as nonvascular cells, differentiated VPCs were more specifically incorporated into developing vasculature mainly as ECs. VPC-derived MCs were also detected in vascular walls. Furthermore, transplantation of differentiated VPCs augmented tumor blood flow in nude mice. These results indicate that a specific vascular contribution in adult neovascularization can be achieved by selective transplantation of ES cell-derived VPCs in appropriate differentiation stages, which should be the basis for vascular regeneration schemes.

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Shear stress attenuates endothelin and endothelin-converting enzyme expression through oxidative stress

Masatsugu, K., Itoh, H., Chun, T. H., Saito, T., Yamashita, J., Doi, K., Inoue, M., Sawada, N., Fukunaga, Y., Sakaguchi, S., Sone, M., Yamahara, K., Yurugi, T. and Nakao, K.

Regul Pept 111 ( 1-3 ) 13 - 9 2003.03

ISSN 0167-0115

Shear stress is known to dilate blood vessels and exert an antiproliferative effect on vascular walls. These effects have partly been ascribed to shear stress-induced regulation of the secretion of endothelium-derived vasoactive substances. In this study, to elucidate the role of shear stress in endothelin production by endothelial cells, we examined the effect of physiological shear stress on the mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1 (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress in an intensity- and time-dependent manner within the physiological range (1.5 to 15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant increase in the intracellular peroxide concentration, and the down-regulation of ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore, when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as well as ET-1 mRNA expression was attenuated in proportion to the concentration of H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE as well as ET to attenuate vascular tone and inhibit the proliferation of vascular smooth muscle cells.

Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration

Yamahara, K., Itoh, H., Chun, T. H., Ogawa, Y., Yamashita, J., Sawada, N., Fukunaga, Y., Sone, M., Yurugi-Kobayashi, T., Miyashita, K., Tsujimoto, H., Kook, H., Feil, R., Garbers, D. L., Hofmann, F. and Nakao, K.

Proc Natl Acad Sci U S A 100 ( 6 ) 3404 - 9 2003.03

ISSN 0027-8424

Natriuretic peptides (NPs), which consist of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as cardiac or vascular hormones that elicit their biological effects by activation of the cGMPcGMP-dependent protein kinase (cGK) pathway. We recently reported that adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed neointimal formation but also accelerated reendothelialization, a required step for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we investigated the therapeutic potential of the NPscGMPcGK pathway for vascular regeneration. In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued. Furthermore, in BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular superoxide production were suppressed compared with control mice. Ischemia-induced angiogenesis was also significantly potentiated in cGK type I Tg mice, but attenuated in cGK type I knockout mice. NPs significantly stimulated capillary network formation of cultured endothelial cells by cGK stimulation and subsequent Erk12 activation. Furthermore, gene transfer of CNP into ischemic muscles effectively accelerated angiogenesis. These findings reveal an action of the NPscGMPcGK pathway to exert multiple vasculoprotective and regenerative actions in the absence of apparent adverse effects, and therefore suggest that NPs as the endogenous cardiovascular hormone can be used as a strategy of therapeutic angiogenesis in patients with tissue ischemia.

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Adrenomedullin promotes proliferation and migration of cultured endothelial cells

Miyashita, K., Itoh, H., Sawada, N., Fukunaga, Y., Sone, M., Yamahara, K., Yurugi, T. and Nakao, K.

Hypertens Res 26 Suppl S93 - 8 2003.02

ISSN 0916-9636

Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0 +/- 8.7% over the controls at 10(-9) mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4 +/- 4.2% over the controls at 10(-7) mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3'5'-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by N(G)-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease.

Lowering of blood pressure improves endothelial dysfunction by increase of nitric oxide production in hypertensive rats

Hatta, T., Nakata, T., Harada, S., Kiyama, M., Moriguchi, J., Morimoto, S., Itoh, H., Sasaki, S., Takeda, K. and Nakagawa, M.

Hypertens Res 25 ( 3 ) 455 - 60 2002.05

ISSN 0916-9636

To investigate the effects of angiotensin converting enzyme inhibitor (ACE-I) and other antihypertensive agents on the nitric oxide (NO) release during hypertension, seven- and fourteen-week-old SHR and deoxycorticosterone acetate (DOCA)-salt rats were treated with hydralazine, manidipine (Ca antagonist) or quinapril (ACE-I) for 3 weeks to lower blood pressure. Systolic blood pressure (SBP) was measured by the tail cuff method once each week. Endothelial cells (ECs) derived from the descending aorta of the treated rats were cultured and NOx levels in culture media were measured with an NO analyzer based on the Griess reaction. In both SHR and DOCA-salt rats, antihypertensive therapy lowered SBP to levels similar to those of control rats. The only exception was quinapril treatment of DOCA-salt rats. Although NOx release by ECs derived from hypertensive rats was improved by antihypertensive therapy, the effect was most pronounced in SHR treated with quinapril. In addition, restoration of NOx release was much more remarkable in younger SHR. NOx release was significantly higher in DOCA-salt rats treated with quinapril than in control rats without reduction of SBP. These results suggest that lowering blood pressure improves release of NO by ECs during hypertension and that the time at which antihypertensive therapy is started is also important to preserve endothelial function. Furthermore, ACE-I is suggested to protect endothelial function by increasing NO production in addition to lowering blood pressure.

[Stroke prevention by statins]

Sawada, N., Itoh, H. and Nakao, K.

Nihon Rinsho 60 ( 5 ) 993 - 1001 2002.05

ISSN 0047-1852

The correlation between stroke incidence and serum lipid level has been equivocal, and conventional lipid-lowering agents such as fibrates were ineffective for stroke prevention. Recent clinical trials for HMG-CoA reductase inhibitors(statins) have demonstrated 20-30% reduction in the risk of cerebrovascular events and mortality in the population with previous coronary heart disease(CHD). The beneficial effect of statins was most evident for thromboembolic stroke, and no significant increase in hemorrhagic events was noted. Equal reduction in stroke risk was observed between hyper- and normocholesterolemic populations, indicating the non-lipid mechanisms of statins. The efficacy and safety of statin treatment make it a promising approach for the management of both CHD and non-CHD patients at high risk of stroke, especially the elderly.

New diagnostic procedure for primary aldosteronism: adrenal venous sampling under adrenocorticotropic hormone and angiotensin II receptor blocker--application to a case of bilateral multiple adrenal microadenomas

Yamahara, K., Itoh, H., Yamamoto, A., Sasano, H., Masatsugu, K., Sawada, N., Fukunaga, Y., Sakaguchi, S., Sone, M., Yurugi, T. and Nakao, K.

Hypertens Res 25 ( 2 ) 145 - 52 2002.03

ISSN 0916-9636

Formerly, the incidence of primary aldosteronism (PA) among patients with hypertension was believed to be less than 1%. However, recent studies have suggested a much higher incidence of 6.59%-14.4% among such patients. These findings suggest that many cases of PA caused by small aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA) have not been properly diagnosed. To make a more accurate diagnosis in such cases, we developed a new diagnostic procedure for localization of PA, namely, adrenal venous sampling under continuous infusion of adrenocorticotropic hormone (ACTH) and administration of angiotensin II receptor blocker (AVS with ACTH and ARB). Here, we confirm the efficacy of this procedure in the case of a 37-year-old male suspected of having PA. The anticipated diagnosis of PA was based on the presence of hypokalemia, low plasma renin activity (PRA), elevated plasma aldosterone concentration (PAC) and left adrenal mass. However, AVS with ACTH and ARB revealed the presence of bilateral multiple adrenal microadenomas. In the new AVS method, neither ACTH nor the renin-angiotensin system (RAS) exert any influence on the plasma aldosterone level, and a more accurate aldosterone secretary state and a more accurate assessment of the aldosterone secretion of both adrenal glands can be recognized than by conventional AVS. Use of this new method should enable identification of additional cases of APA among patients diagnosed with essential hypertension.

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