Hiroshi Koriyama

Hiroshima University, Hirosima, Hiroshima, Japan

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Publications (28)96.51 Total impact

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    ABSTRACT: Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG(-/-) mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG(-/-) mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl2, or H2O2-stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.
    Proceedings of the National Academy of Sciences of the United States of America. 05/2014;
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    ABSTRACT: Periostin is an extracellular matrix glycoprotein and has various cellular effects. Previously, we demonstrated the neuroprotective effects of periostin during the acute stage of cerebral ischemia. However, its expression during the chronic stage remains unknown. Herein, we examined the expression of full-length periostin (periostin 1; Pn1) and its splicing variant lacking exon 17 (periostin 2; Pn2) during the 28 days following transient middle cerebral artery occlusion in mice. Real-time reverse transcription-PCR showed that the expression of Pn2 was dramatically upregulated between days 3 and 28, and the highest expression was observed on day 7. The expression of Pn1 was also increased, but delayed compared with Pn2. Immunohistochemistry showed that periostin was weakly expressed in reactive astrocytes in the peri-infarct region and in microglia/macrophages in infarct regions, on days 3 and 7. Periostin was also expressed around CD31-positive cells in both the peri-infarct and the sub-ventricular zone (SVZ) on days 3 and 7. SOX-2 positive cells, which are neural stem cells, also expressed periostin on day 7. The highest periostin immunoreactivity that occurred co-localized with collagen I and fibronectin in the peri-infarct region between days 7 and 28. Thus, the expression pattern of periostin mRNA was dependent on the splicing variant, and it continued to be expressed up to 28 days after cerebral ischemia. As periostin was expressed in various cells, such as reactive astrocytes/microglia, fibroblasts and neuronal progenitor cells, periostin might be associated with pathophysiology in post-ischemic inflammation and neurogenesis.Hypertension Research advance online publication, 20 March 2014; doi:10.1038/hr.2014.36.
    Hypertension Research 03/2014; · 2.79 Impact Factor
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    ABSTRACT: The increasing prevalence of type 2 diabetes mellitus is associated with a significant economic burden. We developed a dipeptidyl peptidase 4 (DPP4)-targeted immune therapy to increase glucagon-like peptide 1 hormone levels and improve insulin sensitivity for the prevention and treatment of type 2 diabetes mellitus. Immunization with the DPP4 vaccine in C57BL/6J mice successfully increased DPP4 titer, inhibited plasma DPP4 activity, and induced an increase in the plasma glucagon-like peptide 1 level. Moreover, this elevated titer was sustained for 3 mo. In mice fed a high-fat diet, DPP4 vaccination resulted in improved postprandial glucose excursions and insulin sensitivity and, in the diabetic KK-A(y) and db/db mice strains, DPP4 vaccination significantly reduced glucose excursions and increased both plasma insulin and pancreatic insulin content. Importantly, T cells were not activated following challenge with DPP4 itself, which suggests that this vaccine does not induce cell-mediated autoimmunity. Additionally, no significant immune-mediated damage was detected in cells and tissues where DPP4 is expressed. Thus, this DPP4 vaccine may provide a therapeutic alternative for patients with diabetes.
    Proceedings of the National Academy of Sciences 03/2014; · 9.81 Impact Factor
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    ABSTRACT: Vaccines are commonly used as a preventive medicine for infectious diseases worldwide, however, clinical trials on an amyloid beta vaccine for Alzheimer's disease represents a new concept in the field of vaccinations. Several recent studies indicate the potential of therapeutic vaccines as well as classical vaccines as preventive medicines. A number of therapeutic vaccines for cancer have been developed as novel immunotherapies. Their targets are usually specifi c antigens in cancer cells, allowing activated cytotoxic T cells (CTLs) to attach and remove the antigen-presenting cancer cells. Recently, we and others have attempted to develop a therapeutic vaccine against hypertension. The vaccine target is angiotensin II (AngII), and induced anti-AngII antibodies could efficiently ameliorate high blood pressure. However, because AngII is an endogenous hormone, we must avoid the induction of autoimmune diseases by administration of an AngII vaccine. Therefore, our system was used to design a therapeutic vaccine that elicits anti-AngII antibodies without CTL activation against AngII. Because the target antigen itself does not include T cell epitopes, the immunogenic molecule (ie, KLH) provides antigen that supports the activation of T cells. In particular, helper T cells may activate B cells that produce antibodies against our specific antigen. In this review, we will explain our concept of therapeutic vaccines based on our recent data.
    International Heart Journal 03/2014; · 1.23 Impact Factor
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    ABSTRACT: Diabetes mellitus, hypertension and metabolic syndrome are major risk factors for the occurrence of cardiovascular events. In this study, we used spontaneous hypertensive rat (SHR)/NDmcr-cp (cp/cp) (SHRcp) rats as a model for metabolic syndrome to examine the effects of dipeptidyl peptidase (DPP)-4 inhibition on hypertension, glucose metabolism and endothelial dysfunction. First, we confirmed that SHRcp rats showed very severe obesity, hypertension and endothelial dysfunction phenotypes from 14 to 54 weeks of age. Next, we examined whether the DPP-4 inhibitor teneligliptin (10 mg kg(-1) per day per os for 12 weeks) could modify any of these phenotypes. Treatment with teneligliptin significantly improved hyperglycemia and insulin resistance, as evidenced by an oral glucose tolerance test and homeostasis model assessment for insulin resistance, respectively. Teneligliptin showed no effects on systolic blood pressure or heart rate. In regard to endothelial function, the vasodilator response to acetylcholine was significantly impaired in SHRcp rats when compared with WKY rats. Long-term treatment with teneligliptin significantly attenuated endothelial dysfunction through the upregulation of endothelium-derived nitric oxide synthase mRNA. These results demonstrate that long-term treatment with teneligliptin significantly improved endothelial dysfunction and glucose metabolism in a rat model of metabolic syndrome, suggesting that teneligliptin treatment might be beneficial for patients with hypertension and/or diabetes.Hypertension Research advance online publication, 13 March 2014; doi:10.1038/hr.2014.53.
    Hypertension Research 03/2014; · 2.79 Impact Factor
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    ABSTRACT: OBJECTIVE: Vascular calcification is accelerated by hypertension and also contributes to hypertension; however, it is an enigma why hypertension and vascular calcification are a vicious spiral. The present study elucidates the cross-talk between renin-angiotensin II system and receptor activator of nuclear factor-κB ligand (RANKL) system in vascular calcification.Approach and Results-Angiotensin (Ang) II (10(-7) mol/L) significantly increased calcium deposition as assessed by Alizarin Red staining, associated with a significant increase in the expression of RANKL, RANK, and bone-related genes, such as cbfa1 and msx2, in human aortic vascular smooth muscle cells. Infusion of Ang II (100 ng/kg per minute) in ovariectomized ApoE(-/-) mice under high-fat diet significantly increased the expression of RANKL system and calcification in vivo, whereas administration of Ang II receptor blocker (olmesartan, 3 mg/kg per day) decreased the calcification and bone markers' expression. In addition, male OPG(-/-) mice showed a significant increase in vascular calcification followed by Ang II infusion as compared with wild type. Conversely, RANKL significantly increased Ang II type 1 receptor and angiotensin II-converting enzyme expression in vascular smooth muscle cells via extracellular signal-regulated protein kinase phosphorylation. CONCLUSIONS: The present study demonstrated that Ang II significantly induced vascular calcification in vitro and in vivo through RANKL activation. In addition, RANKL activated renin-angiotensin II system, especially angiotensin II-converting enzyme and Ang II type 1 receptor. Cross-talk between renin-angiotensin II system and RANKL system might work as a vicious cycle to promote vascular calcification in atherosclerosis. Further studies to inhibit renin-angiotensin II system and RANKL may provide new therapeutic options to prevent and regress vascular calcification.
    Arteriosclerosis Thrombosis and Vascular Biology 04/2013; · 6.34 Impact Factor
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    ABSTRACT: The effectiveness of angioplasty and stenting in intracranial atherosclerotic diseases is controversial due to high rates of delayed restenosis and hemorrhage compared with extracranial arteries. However, the mechanisms underlying these differences are still unclear, because their pathophysiology is yet to be examined. To address this issue, we established a novel vascular injury model in the intracranial internal carotid arteries (IICAs) in mice, and analyzed the remodeling process in comparison to that of the femoral arteries (FAs). In IICAs, neointimal hyperplasia was observed from day 14 and grew until day 56. Although smooth muscle cells (SMCs) emerged in the neointima from day 28, SMCs in the injured media were continuously lost with eventual extinction of the media. Re-endothelialization was started from day 7 and completed on day 28. Accumulation of macrophages was continued in the adventitia until day 56. Compared with FAs, the following points are unique in IICAs: (1) delayed continuous formation of neointima; (2) accumulation of macrophages in the media on day 14; (3) continuous loss of SMCs in the media followed by extinction of the media itself; and (4) continuously growing adventitia. These pathophysiologic differences might be associated with unfavorable outcomes in percutaneous transluminal angioplasty and stenting in intracranial arteries.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 April 2013; doi:10.1038/jcbfm.2013.62.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2013; · 5.46 Impact Factor
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    ABSTRACT: Lipoprotein(a) [Lp(a)] is an unique lipoprotein consisting of the glycoprotein apolipoprotein(a) [apo(a)] in low-density lipoprotein. Although Lp(a) is a well-known independent risk factor for cardiovascular disease; however, there is no drugs to decrease plasma Lp(a) level. Thus, to inhibit the biological activity of Lp(a), we developed DNA vaccine for apo(a) by the targeting to the selected 12 hydrophilic amino acids in the kringle-4 type 2 domain of apo(a). Hepatitis B virus core protein was used as an epitope carrier to enhance the immunogenicity. Intramuscular immunization with apo(a) vaccine resulted in the significant inhibition of neointima formation in carotid artery ligation model using Lp(a) transgenic mice, associated with anti-apo(a) antibody and decrease in vascular Lp(a) deposition. Overall, this study provided the first evidence that the pro-atherosclerotic actions of Lp(a) could be prevented by DNA vaccine directed against apo(a), suggesting a novel therapeutic strategy to treat cardiovascular diseases related to high Lp(a).
    Scientific Reports 04/2013; 3:1600. · 5.08 Impact Factor
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    ABSTRACT: We developed DNA vaccine for vascular endothelial growth factor (VEGF), which may provide the therapeutic option instead of anti-VEGF antibody, bevacizumab. Plasmid containing VEGF mini-gene was constructed in the insertion of B-cell epitope of Hepatitis B core protein [HBc-VEGF], which was an epitope carrier. High titer of anti-VEGF antibody was observed in BALB/c mice which were intramuscularly immunized with HBc-VEGF by electropolator. In mice inoculated with colon 26 cells, tumor volume and microvessel density was decreased in HBc-VEGF with a significant prolonged survival. Co-treatment of purified IgG from immunized mice with HBc-VEGF showed in vitro neutralizing activity for VEGF-induced ERK phosphorylation and tube formation in cultured endothelial cells. Furthermore, intravitreally injection of this purified IgG reduced the neovessel formation in the mouse oxygen-induced retinopathy and laser-induced choroidal neovascularization models. These results first provided that DNA vaccine against VEGF possessed the anti-angiogenic effect, leading to prolonged survival in mouse cancer model.
    Scientific Reports 01/2013; 3:3380. · 5.08 Impact Factor
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    ABSTRACT: Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer's disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.
    PLoS ONE 01/2013; 8(3):e60493. · 3.53 Impact Factor
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    ABSTRACT: Gene therapy and cell-based therapy have emerged as novel therapies to promote therapeutic angiogenesis in critical limb ischemia (CLI) caused by peripheral artery disease (PAD). Although researchers initially focused on gene therapy using proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factors (HGF), cell therapy using bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (BMMSCs), G-CSF-mobilized peripheral blood mononuclear cells (M-PBMNCs), and endothelial progenitor cells (EPCs) have also been extensively studied. Based on the elaborate studies and favorable results of basic research, some clinical phase I/II trials have been performed, and the results demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI. However, the phase 3 clinical trials have thus far been limited to gene therapy using the HGF gene. Further studies using well-designed larger placebo-controlled and long-term randomized control trials (RCTs) will clarify the effectiveness of gene therapy and cell-based therapy for the treatment of CLI. Furthermore, the development of efficient gene transfer systems and effective methods for keeping transplanted cells healthy will make these novel therapies more effective and ease the symptoms of CLI.
    BioMed research international. 01/2013; 2013:186215.
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    ABSTRACT: The γ-secretase complex (which contains presenilins, nicastrin, anterior pharynx defective-1, and presenilin enhancer-2) cleaves type I transmembrane proteins, including Notch and amyloid precursor protein. Dysregulated γ-secretase activity has been implicated in the pathogenesis of Alzheimer's disease, stroke, atherosclerosis, and cancer. Tight regulation of γ-secretase activity is required for normal physiology. Here, we isolated HIG1 (hypoxia inducible gene 1, domain member 1A) from a functional screen of γ-secretase inhibitory genes. HIG1 was highly expressed in the brain. Interestingly, HIG1 was localized to the mitochondria and was directly bound to γ-secretase components on the mitochondrial membrane in SK-N-SH neuroblastoma cells. Overexpresssion of HIG1 attenuated hypoxia-induced γ-secretase activation on the mitochondrial membrane and the accumulation of intracellular amyloid β. This accumulation was accompanied by hypoxia-induced mitochondrial dysfunction. The latter half domain of HIG1 was required for binding to the γ-secretase complex and suppression of γ-secretase activity. Moreover, depletion of HIG1 increased γ-secretase activation and enhanced hypoxia-induced mitochondrial dysfunction. In summary, HIG1 is a novel modulator of the mitochondrial γ-secretase complex, and may play a role in the maintenance of normal mitochondrial function.
    The FASEB Journal 02/2012; 26(6):2306-17. · 5.70 Impact Factor
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    Dyslipidemia - From Prevention to Treatment, 02/2012; , ISBN: 978-953-307-904-2
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    ABSTRACT: Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.
    Molecular Medicine Reports 09/2011; 5(1):37-40. · 1.17 Impact Factor
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    ABSTRACT: Both osteoporosis and high blood pressure are major diseases in aging populations. Recent studies demonstrated that some antihypertensive drugs reduced the risk of bone fracture in elderly patients. Although calcium channel blockers (CCB) are widely used as first-line antihypertensive agents, there is no evidence that they prevent osteoporosis. In this study, we investigated the effects of two types of CCB on bone metabolism: cilnidipine (L-/N-type CCB), which suppresses norepinephrine release from the sympathetic nerve, and amlodipine (L-type CCB). In ovariectomized female spontaneous hypertensive rats, administration of cilnidipine, but not amlodipine, resulted in a significant increase in the ratio of alkaline phosphatase to tartrate-resistant acid phosphatase (TRAP) and a decrease in the number of osteoclasts, as assessed by TRAP staining in the proximal tibia. Bone mineral density, moreover, was significantly higher in the cilnidipine group as compared with the amlodipine group and was associated with a significant decrease in a urinary collagen degradation product (deoxypyridinoline). The degree of prevention of osteoporosis by cilnidipine was similar to that of carvedilol (a β-blocker) because β-blockers reduce fracture risks though the inhibition of osteoclast activation. Interestingly, these effects cannot be attributed to the reduction of blood pressure because all three drugs significantly decreased blood pressure. In contrast, both cilnidipine and carvedilol, but not amlodipine, significantly decreased heart rate, indicating that both cilnidipine and carvedilol suppressed sympathetic nervous activity. Overall, our present data showed that cilnidipine (L-/N-type CCB) ameliorated osteoporosis in ovariectomized hypertensive rats. These pleiotropic effects of antihypertensive drugs such as cilnidipine and carvedilol might provide additional benefits in the treatment of hypertensive postmenopausal women.
    Hypertension Research 09/2011; 35(1):77-81. · 2.79 Impact Factor
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    ABSTRACT: Treatment with angiotensin type 1 receptor blockers (ARBs) is known to improve renal dysfunction and glucose metabolism in obese diabetic animal models and humans. This study examined the effects of irbesartan, a unique ARB with PPARγ activation, on endothelial dysfunction, renal dysfunction, abnormal lipid profile, and liver dysfunction in obese fa/fa Zucker diabetic fatty (ZDF) rats. ZDF rats were administered irbesartan (30 mg/kg/day p.o.) for 12 weeks. Blood pressure, glucose metabolism, lipid profile and renal function were measured every 4 weeks. Response of mesenteric artery rings to acetylcholine was also evaluated as an index of endothelial function after 12 weeks of treatment. Although irbesartan did not affect glucose and insulin levels in both glucose and insulin tolerance tests, decreases in systolic blood pressure, dyslipidemia, and urinary protein excretion were noted from 4 weeks after the start of treatment and continued until 12 weeks. Endothelial and liver dysfunctions were also improved after 12 weeks of treatment. Compared to previous reports showing the effects of irbesartan at later time points such as 6 or 12 months, the present study demonstrated that a low-dose of irbesartan had favorable effects from the early period of treatment, independent of glucose metabolism. Our findings suggest that a low-dose of irbesartan improves diabetic complications quickly after starting treatment, and may support the use of irbesartan for preventing progression of diabetic complications.
    Experimental and therapeutic medicine 01/2011; 2(5):957-961. · 0.34 Impact Factor
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    ABSTRACT: Peripheral arterial disease (PAD) is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. However, little is known about the genetic basis of PAD. To elucidate this, we performed a two-staged genome-wide association study in Japanese individuals. We initially tested 222,285 single-nucleotide polymorphisms (SNPs). After the first screening in a panel of 195 PAD cases and 1,358 controls, 2,696 SNPs (1.2%) were further genotyped in the second screening using another panel of 699 PAD cases and 1540 controls. In both screenings, controls were subjects affected with some diseases other than PAD. When analyzed in the combined panel, the strongest signal of PAD association was observed at rs1902341 in the intron of OSBPL10 (p=4.7E-7 for trend test; OR=1.31, 95% CI 1.18-1.46). Also, PAD was modestly associated at several other loci such as rs2554503 in CSMD1 (p=5.7E-5; OR=1.32, 95% CI 1.15-1.51) or rs235243 in VSP13D (p=0.04; OR=1.18, 95% CI 1.01-1.37). Our genome-wide exploration identified suggestive evidence of PAD association at the OSBPL10 locus. Because the association has not reached a genome-wide significant level, further replication study is warranted for verification in the Japanese population.
    Journal of atherosclerosis and thrombosis 10/2010; 17(10):1054-62. · 2.93 Impact Factor
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    ABSTRACT: A series of clinical studies have shown that thiazide diuretics (TD) might reduce the risk of bone fractures. We also recently demonstrated that angiotensin receptor blockers (ARB) ameliorated ovariectomy (OVX)-induced osteoporosis in a hypertensive rat model. In this study, we examined whether a combination of TD and ARB might have additional effects on osteoporosis in a hypertensive rat model. In spontaneous hypertensive rats, estrogen deficiency induced by OVX resulted in a significant increase in osteoclast activation as assessed by tartrate-resistant acid phosphatase (TRAP) activity in the tibia, accompanied by a significant decrease in bone mineral density (BMD) evaluated by dual-energy X-ray absorptiometry and an increase in urinary deoxypyridinoline. Treatment with high-dose ARB, valsartan (3 mg Kg-1day-1), attenuated the OVX-induced decrease in BMD and increased TRAP activity and urinary deoxypyridinoline, whereas low-dose ARB, valsartan (1 mg Kg-1day-1), or low-dose TD, hydrochlorothiazide (0.2 mg Kg-1day-1), did not. Of importance, administration of low-dose valsaltan in combination with hydrochlorothiazide significantly decreased the magnitude of bone mineral loss compared with the effect of administration of high-dose valsartan alone. These results demonstrated that treatment with TD in combination with ARB attenuated osteoporosis additionally in a hypertensive rat model.
    Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents) 08/2010; 10(3):115-122.
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    ABSTRACT: Arterial calcification and osteoporosis are associated in postmenopausal women. RANK (the receptor activator of nuclear factor kappaB), RANKL (RANK ligand), and osteoprotegerin are key proteins in bone metabolism and have been found at the site of aortic calcification. The role of these proteins in vasculature, as well as the contribution of estrogen to vascular calcification, is poorly understood. To clarify the mechanism of RANKL system to vascular calcification in the context of estrogen deficiency. RANKL induced the calcification inducer bone morphogenetic protein-2 by human aortic endothelial cells (HAECs) and decreased the calcification inhibitor matrix Gla protein (MGP) in human aortic smooth muscle cells (HASMCs), as quantified by real-time PCR and Western blot analysis. RANKL also induced bone-related gene mRNA expression and calcium deposition (Alizarin red staining) followed by the osteogenic differentiation of HASMCs. Estrogen inhibited RANKL signaling in HAECs and HASMCs mainly through estrogen receptor alpha. Apolipoprotein E-deficient mice fed with Western high-fat diet for 3 months presented atherosclerotic calcification (Oil red and Alizarin red staining) and osteoporosis (microcomputed tomographic analysis) after ovariectomy and increased expression of RANKL, RANK, and osteopontin in atherosclerotic lesion, as detected by in situ hybridization. Estrogen replacement inhibited osteoporosis and the bone morphogenetic protein osteogenic pathway in aorta by decreasing phosphorylation of smad-1/5/8 and increasing MGP mRNA expression. RANKL contributes to vascular calcification by regulating bone morphogenetic protein-2 and MGP expression, as well as bone-related proteins, and is counteracted by estrogen in a receptor-dependent manner.
    Circulation Research 08/2010; 107(4):466-75. · 11.86 Impact Factor
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    ABSTRACT: The oxysterol hypothesis of cholesterol homeostasis states that oxysterol mediates feedback regulation of cholesterol biosynthesis. Oxysterol-binding proteins have been implicated in the control of lipid synthesis and metabolism. In a genome-wide case-control association study in Japanese individuals, we found that the three single-nucleotide polymorphisms (SNPs) with the smallest P-values were located in the fifth intronic region of the oxysterol-binding protein-like 10 (OSBPL10) gene. In this study, we examined the association between polymorphisms in the OSBPL10 gene and risk factors for the metabolic syndrome in the Tanno and Sobetsu Study. We selected four SNPs, including three non-coding SNPs in intron 5 and a coding SNP (D254N) in exon 6. Genotype frequencies of the polymorphisms satisfied the conditions for Hardy-Weinberg equilibrium. We found that the low-density lipoprotein (LDL) cholesterol of individuals with the rs2290532 (D254N) polymorphism was significantly greater in subjects with the CC+CT genotype than in subjects with the TT genotype (124.3+/-1.3 vs. 111.6+/-4.1 mg per 100 ml, P=0.009). However, there were no significant differences in systolic or diastolic blood pressure, high-density lipoprotein cholesterol or triglyceride levels. Multiple regression analysis showed that rs2290532 (D254N) was associated with LDL cholesterol independent of age, sex or body mass index. Comparison of the genotype frequency in both groups indicated that the genotype associated with low risk (TT) reduced the risk of hyper-LDL cholesterolemia significantly (P=0.003), with an odds ratio of 0.35 (95% confidence interval=0.17-0.76). Overall, the rs2290532 (D254N) polymorphism in OSBPL10 may predispose individuals with this SNP to hyper-LDL cholesterolemia.
    Hypertension Research 03/2010; 33(5):511-4. · 2.79 Impact Factor

Publication Stats

160 Citations
96.51 Total Impact Points

Institutions

  • 2013
    • Hiroshima University
      Hirosima, Hiroshima, Japan
  • 2007–2013
    • Osaka University
      • • Division of Gene Therapy Science
      • • Division of Geriatric Medicine and Nephrology
      Suika, Ōsaka, Japan
  • 2006–2010
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan