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Mingjie Ma,
Ken Uekawa,
Yu Hasegawa,
Takashi Nakagawa,
Tetsuji Katayama,
Daisuke Sueta,
Kensuke Toyama,
Keiichiro Kataoka, Nobutaka Koibuchi,
Jun-Ichi Kuratsu,
Shokei Kim-Mitsuyama
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ABSTRACT: This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90minutes of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24hours after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation.
Brain research 04/2013; · 2.46 Impact Factor
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Daisuke Sueta,
Keiichiro Kataoka, Nobutaka Koibuchi,
Kensuke Toyama,
Ken Uekawa,
Tetsuji Katayama,
Ma Mingjie,
Takashi Nakagawa,
Hidefumi Waki,
Masanobu Maeda,
Osamu Yasuda,
Kunihiko Matsui,
Hisao Ogawa,
Shokei Kim-Mitsuyama
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ABSTRACT: This study was performed to determine the characteristics and mechanism of hypertension in SHR/NDmcr-cp(+/+) rats (SHRcp), a new model of metabolic syndrome, with a focus on the autonomic nervous system, aldosterone, and angiotensin II.
We measured arterial blood pressure (BP) in SHRcp by radiotelemetry combined with spectral analysis using a fast Fourier transformation algorithm and examined the effect of azilsartan, an AT1 receptor blocker. Compared with control Wistar-Kyoto rats (WKY) and SHR, SHRcp exhibited a nondipper-type hypertension and displayed increased urinary norepinephrine excretion and increased urinary and plasma aldosterone levels. Compared with WKY and SHR, SHRcp were characterized by an increase in the low-frequency power (LF) of systolic BP and a decrease in spontaneous baroreflex gain (sBRG), indicating autonomic dysfunction. Thus, SHRcp are regarded as a useful model of human hypertension with metabolic syndrome. Oral administration of azilsartan once daily persistently lowered BP during the light period (inactive phase) and the dark period (active phase) in SHRcp more than in WKY and SHR. Thus, angiotensin II seems to be involved in the mechanism of disrupted diurnal BP rhythm in SHRcp. Azilsartan significantly reduced urinary norepinephrine and aldosterone excretion and significantly increased urinary sodium excretion in SHRcp. Furthermore, azilsartan significantly reduced LF of systolic BP and significantly increased sBRG in SHRcp.
These results strongly suggest that impairment of autonomic function and increased aldosterone in SHRcp mediate the effect of angiotensin II on circadian blood pressure rhythms.
Journal of the American Heart Association. 01/2013; 2(3):e000035.
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ABSTRACT: The pharmacological advantage of combination of an angiotensin receptor blocker (ARB) and a calcium-channel blocker (CCB) is not fully defined. This study was undertaken to elucidate the potential benefit of their combination in metabolic syndrome.
SHR/NDmcr-cp (SHRcp), a rat model of human metabolic syndrome, were divided into four groups, and were administered (i) vehicle, (ii) candesartan (an ARB) 0.3 mg/kg/day, (iii) amlodipine (a CCB) 3 mg/kg/day, and (iv) candesartan 0.3 mg/kg/day plus amlodipine 3 mg/kg/day, for 4 weeks.
Candesartan, amlodipine, or their combination significantly ameliorated the impairment of vascular endothelium-dependent relaxation with acetylcholine in SHRcp. However, the impairment of insulin-induced vasodilation in SHRcp was partially improved by candesartan alone, but not by amlodipine alone. Interestingly, amlodipine added to candesartan synergistically enhanced the improvement of impaired insulin-induced vasodilation by candesartan, indicating the synergistic improvement of vascular insulin resistance by the combination of these drugs. Candesartan alone, but not amlodipine alone, significantly attenuated vascular superoxide and NADPH oxidase subunit p22phox in SHRcp. Amlodipine added to candesartan synergistically enhanced the reduction of vascular p22phox levels and superoxide by candesartan in SHRcp, suggesting the association of vascular insulin resistance with oxidative stress. Furthermore, the combination of candesartan with amlodipine synergistically decreased the increase in visceral adipocyte size, serum free-fatty acid, and tumor necrosis factor-α in SHRcp.
ARB and CCB combination synergistically ameliorated vascular insulin resistance in metabolic syndrome, being associated with the synergistic attenuation of vascular oxidative stress and metabolic disorders.
American Journal of Hypertension 03/2012; 25(6):704-10. · 3.18 Impact Factor
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Hiroki Hayashi,
Hironori Nakagami,
Makiko Takeichi,
Munehisa Shimamura, Nobutaka Koibuchi,
Eiji Oiki,
Naoyuki Sato,
Hiroshi Koriyama,
Masaki Mori,
Rodriguez Gerardo Araujo,
Akito Maeda,
Ryuichi Morishita,
Katsuto Tamai,
Yasufumi Kaneda
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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. · 5.71 Impact Factor
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ABSTRACT: Although periostin, an extracellular matrix glycoprotein, plays pivotal roles in survival, migration, and regeneration in various cells, its expression and function in the brain are still unknown. Here, we investigated the expression and role of periostin in the ischemic brain.
Expression of full-length periostin (periostin 1 [Pn1]) and its splicing variant lacking exon 17 (periostin 2 [Pn2]) was examined by real-time reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining in male C57BL6/J mice. The actions of periostin were examined in adult primary neuronal culture and in a transient middle cerebral artery occlusion (tMCAo) model.
Expression of Pn2, but not of Pn1, mRNA was markedly changed after tMCAo. Pn2 mRNA was decreased in the ischemic core at 3 hours after ischemia. At 24 hours, Pn2 mRNA was significantly increased in both the peri-ischemic and ischemic regions. Periostin was mainly observed in neurons in normal brain. However, neuronal expression of periostin was decreased temporarily in the ischemic region, but increased in astrocytes and around endothelial cells at 24 hours after tMCAo. Of importance, intracerebroventricular injection of Pn2 resulted in a significant reduction in infarct volume at 24 hours after tMCAo associated with phosphorylation of Akt. Also, the Pn2-treated mice survived longer until 1 week after tMCAo. Pn2 significantly inhibited neuronal death under hypoxia and stimulated neurite outgrowth.
Here, we demonstrated that periostin was expressed in the brain, and exogenous Pn2 exhibited neuroprotective effects and accelerated neurite outgrowth. Additional studies on periostin may provide new insights into the treatment of ischemic stroke.
Stroke 02/2012; 43(4):1108-14. · 5.73 Impact Factor
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ABSTRACT: The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.
PLoS ONE 01/2012; 7(6):e39162. · 4.09 Impact Factor
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ABSTRACT: This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury.
Hypertension Research 11/2011; 35(2):194-200. · 2.58 Impact Factor
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ABSTRACT: The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.
Hypertension 08/2011; 58(4):635-42. · 6.21 Impact Factor
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Yi-Fei Dong,
Keiichiro Kataoka,
Yoshiko Tokutomi,
Hisato Nako,
Taishi Nakamura,
Kensuke Toyama,
Daisuke Sueta, Nobutaka Koibuchi,
Eiichiro Yamamoto,
Hisao Ogawa,
Shokei Kim-Mitsuyama
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ABSTRACT: The optimum antihypertensive treatment for prevention of hypertensive stroke has yet to be elucidated. This study was undertaken to examine the benefit of a combination of valsartan, an angiotensin II type 1 (AT1) receptor blocker, and amlodipine, a calcium channel blocker, in prevention of high-salt-induced brain injury in hypertensive rats. High-salt-loaded stroke-prone spontaneously hypertensive rats (SHRSPs) were given 1) vehicle, 2) valsartan (2 mg/kg/day), 3) amlodipine (2 mg/kg/day), or 4) a combination of valsartan and amlodipine for 4 weeks. The effects on brain injury were compared between all groups. High-salt loading in SHRSPs caused the reduction of cerebral blood flow (CBF), cerebral hypoxia, white matter lesions, glial activation, AT1 receptor up-regulation, endothelial nitric-oxide synthase (eNOS) uncoupling, inducible nitric-oxide synthase induction, and nitroxidative stress. Valsartan, independently of blood pressure, enhanced the protective effects of amlodipine against brain injury, white matter lesions, and glial activation in salt-loaded SHRSPs. These beneficial effects of valsartan added to amlodipine were associated with an additive improvement in CBF and brain hypoxia because of an additive improvement in cerebral arteriolar remodeling and vascular endothelial dysfunction. Furthermore, valsartan added to amlodipine enhanced the attenuation of cerebral nitroxidative stress through an additive suppression of eNOS uncoupling. Valsartan, independently of blood pressure, augmented the protective effects of amlodipine against brain injury in salt-loaded hypertensive rats through an improvement in brain circulation attributed to nitroxidative stress. Our results suggest that the combination of valsartan and amlodipine may be a promising strategy for the prevention of salt-related brain injury in hypertensive patients.
Journal of Pharmacology and Experimental Therapeutics 08/2011; 339(2):358-66. · 3.83 Impact Factor
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ABSTRACT: Periostin (PN), a secreted adhesion-related protein expressed in the periosteum and periodontal ligaments, acts as a critical regulator of the formation and maintenance of bone and teeth, and also plays an important role in tumorigenesis. Although PN is highly expressed in various types of human cancers, its function is still unclear. In this study, we focused on the exon 17 region of PN, which is alternatively spliced out. To investigate the function of full-length PN with exon 17, we produced a neutralizing antibody (PN1-Ab) against the peptide encoded by exon 17. In vivo, administration of PN1-Ab significantly inhibited the growth of primary tumors as well as metastatic tumors, associated with prevention of bone destruction, resulting in increased survival of mice. Consistent with in vivo data, the present in vitro study demonstrated that addition of full-length PN significantly inhibited cell adhesion and detached adherent cells, while PN1-Ab inhibited the action of PN in a dose-dependent manner. In addition, PN1-Ab significantly inhibited the proliferation, migration and invasion of 4T1 mouse breast cancer cells, which produced PN. Interestingly, PN1-Ab also inhibited the differentiation of osteoclasts. Overall, the present study demonstrated that PN plays a pivotal role in the progression and metastasis of breast cancer. Since administration of PN1-Ab prolonged cell survival through inhibition of the progression and metastasis of 4T1 cells, further development of the PN1-Ab such as generation of a humanized antibody may provide a new therapeutic agent against breast cancer.
International Journal of Molecular Medicine 08/2011; 28(2):181-6. · 1.98 Impact Factor
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Taishi Nakamura,
Keiichiro Kataoka,
Yoshiko Tokutomi,
Hisato Nako,
Kensuke Toyama,
Yi-Fei Dong, Nobutaka Koibuchi,
Eiichiro Yamamoto,
Osamu Yasuda,
Hisao Ogawa,
Shokei Kim-Mitsuyama
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ABSTRACT: The present study was undertaken to examine the role of endothelial nitric oxide synthase (eNOS) in salt-sensitive renal injury.
The effects of high-salt diet on renal injury were compared between wild-type and eNOS-/- mice. To examine the role of glomerular angiotensin II and oxidative stress, high-salt fed eNOS-/- mice were given irbesartan, an angiotensin receptor blocker, or tempol, an antioxidant.
Four weeks of high-salt diet in wild-type mice, which rapidly caused glomerular eNOS activation and subsequent increase in nitric oxide, did not at all induce renal injury, indicating that wild-type mice are salt-resistant. On the contrary, high-salt diet in eNOS-/- mice, which little increased nitric oxide, rapidly increased urinary albumin excretion, followed by glomerular macrophage infiltration and glomerular sclerosis. Thus, eNOS deficiency caused salt-sensitive glomerular injury. Salt-induced glomerular injury in eNOS-/- mice was preceded by rapid enhancement of glomerular superoxide followed by enhancement of glomerular endothelial angiotensinogen and angiotensin II. Irbesartan and tempol, independently of blood pressure, markedly prevented salt-induced glomerular injury in eNOS-/- mice, and these protective effects were attributed to the attenuation of glomerular oxidative stress and glomerular angiotensinogen-derived angiotensin II.
We propose that eNOS dysfunction plays a causative role in salt-induced glomerular injury, through augmentation of glomerular oxidative stress-induced angiotensinogen.
Journal of hypertension 06/2011; 29(8):1528-35. · 4.02 Impact Factor
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ABSTRACT: Both angiotensin II (Ang II) and transforming growth factor (TGF)-β1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-β1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-β axis in renal cells. In cultured human mesangial cells, TGF-β1 increased angiotensin type 1 receptor (AT(1)R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-β1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-β pathway, because Ang II increased TGF-β expression. In contrast, HGF significantly attenuated the increase in AT(1)R gene expression, and inhibited the decrease in PTEN induced by TGF-β1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-β1-induced AT(1)R expression by HGF. These data suggest that HGF attenuated TGF-β1-induced AT(1)R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT(1)R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-β1-AT(1)R, mediating the inhibition of PTEN.
Hypertension 06/2011; 58(2):190-6. · 6.21 Impact Factor
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Yi-Fei Dong,
Keiichiro Kataoka,
Yoshiko Tokutomi,
Hisato Nako,
Taishi Nakamura,
Kensuke Toyama,
Daisuke Sueta, Nobutaka Koibuchi,
Eiichiro Yamamoto,
Hisao Ogawa,
Shokei Kim-Mitsuyama
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ABSTRACT: The purpose of this work was to test whether brain-penetrating angiotensin-converting enzyme (ACE) inhibitors (e.g., perindopril), as opposed to non-brain-penetrating ACE inhibitors (e.g., enalapril and imidapril), may reduce the cognitive decline and brain injury in Alzheimer's disease (AD). We first compared the effect of perindopril, enalapril, and imidapril on cognitive impairment and brain injury in a mouse model of AD induced by intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)₁₋₄₀. Perindopril, with significant inhibition of hippocampal ACE, significantly prevented cognitive impairment in this AD mouse model. This beneficial effect was attributed to the suppression of microglia/astrocyte activation and the attenuation of oxidative stress caused by iNOS induction and extracellular superoxide dismutase down-regulation. In contrast, neither enalapril nor imidapril prevented cognitive impairment and brain injury in this AD mouse. We next examined the protective effects of perindopril on cognitive impairment in PS2APP-transgenic mice overexpressing Aβ in the brain. Perindopril, without affecting brain Aβ deposition, significantly suppressed the increase in hippocampal ACE activity and improved cognition in PS2APP-transgenic mice, being associated with the suppression of hippocampal astrocyte activation and attenuation of superoxide. Our data demonstrated that the brain-penetrating ACE inhibitor perindopril, as compared to non-brain-penetrating ACE inhibitors, protected against cognitive impairment and brain injury in experimental AD models.
The FASEB Journal 05/2011; 25(9):2911-20. · 5.71 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator for morphogenic tissue interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed in vascular cells and cardiac myocytes. On the other hand, recently, we demonstrated that HGF plasmid DNA transfer significantly improves the size of ulcer in patients with peripheral artery disease (PAD) at Phase III clinical trial, while vascular endothelial growth factor (VEGF) gene therapies for PAD at Phase III have not been succeeded yet. To further investigate this difference between HGF and VEGF, we showed that HGF but not VEGF improves the senescence EPC against oxidative stress through the inhibition of rac1. Moreover, we reported that HGF promotes SHIP-2 translocation from epithelial growth factor receptor (EGFR) to c-Met, and it would protect oxidative stress through EGFR degradation. By this anti-oxidative and anti-senescence effects of HGF would maintain the vessel so long in patients with PAD who receive much oxidative stress in real world. In this report, we discuss a potential therapeutic strategy using HGF in cardiovascular diseases.
Current Signal Transduction Therapy 04/2011; 6(2):221-227. · 0.50 Impact Factor
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ABSTRACT: The progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA-positive myofibroblasts producing large amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Although hepatocyte growth factor (HGF) improved renal fibrosis in various models, the molecular mechanisms involved are not yet fully understood.
In this study, the molecular mechanisms of the inhibition of fibrosis by HGF was examined using HGF transgenic mice (HGF-Tg) with angiotensin II (Ang II) infusion in 4 weeks models. HGF-Tg mice showed significantly decreased Ang II-induced renal fibrosis and lesser numbers of interstitial myofibroblasts, whereas the antifibrotic effect of HGF was abrogated using HGF-neutralizing antibody. The antifibrotic action in HGF-Tg mice was concordant with a decrease in TGF- β1, collagen type I and IV mRNA expression and an increase in MMP-2 and MMP-9 expression. Furthermore, HGF-Tg mice treated with Ang II showed apoptosis of myofibroblasts. To further investigate the antifibrotic effect of HGF, cultured human mesangial cells were used. HGF induced apoptosis of myofibroblast. Inhibition of the FAK-ERK-MMP signaling cascade by specific inhibitor or siRNA significantly decreased HGF-induced myofibroblast apoptosis.
The present study demonstrates that the increase in metalloproteinases through FAK-ERK signaling by HGF promotes myofibroblast apoptosis. Activation of metalloproteinases by HGF in the fibrotic kidney might be considered to attenuate the progression of CKD.
Journal of hypertension 12/2010; 28(12):2454-61. · 4.02 Impact Factor
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Yasutomi Higashikuni,
Julie Sainz,
Kazuto Nakamura,
Minoru Takaoka,
Soichiro Enomoto,
Hiroshi Iwata,
Makoto Sahara,
Kimie Tanaka, Nobutaka Koibuchi,
Sumito Ito,
Hiroyuki Kusuhara,
Yuichi Sugiyama,
Yasunobu Hirata,
Ryozo Nagai,
Masataka Sata
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ABSTRACT: To clarify the impact of breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) expression on cardiac repair after myocardial infarction (MI).
The ATP-binding cassette transporter BCRP1/ABCG2 is expressed in various organs, including the heart, and may regulate several tissue defense mechanisms. BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8- to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knockout (KO) mice by ligating the left anterior descending artery. At 28 days after MI, the survival rate was significantly lower in KO mice than in WT mice because of cardiac rupture. Echocardiographic, hemodynamic, and histological assessments showed that ventricular remodeling was more deteriorated in KO than in WT mice. Capillary, myofibroblast, and macrophage densities in the peri-infarction area at 5 days after MI were significantly reduced in KO compared with WT mice. In vitro experiments demonstrated that inhibition of BCRP1/ABCG2 resulted in accumulation of intracellular protoporphyrin IX and impaired survival of microvascular endothelial cells under oxidative stress. Moreover, BCRP1/ABCG2 inhibition impaired migration and tube formation of endothelial cells.
BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function.
Arteriosclerosis Thrombosis and Vascular Biology 11/2010; 30(11):2128-35. · 6.37 Impact Factor
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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. · 9.49 Impact Factor
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ABSTRACT: Neointimal hyperplasia contributes to atherosclerosis and restenosis after percutaneous coronary intervention. Vascular injury in each of these conditions results in the release of mitogenic growth factors and hormones that contribute to pathological vascular smooth muscle cell growth and inflammation. Hepatocyte growth factor (HGF) is known as an antiinflammatory growth factor, although it is downregulated in injured tissue. However, the precise mechanism how HGF reduces inflammation is unclear.
To elucidate the mechanism how HGF and its receptor c-Met reduces angiotensin II (Ang II)-induced inflammation.
HGF reduced Ang II-induced vascular smooth muscle cell growth and inflammation by controlling translocation of SHIP2 (Src homology domain 2-containing inositol 5'-phosphatase 2), which led to Ang II-dependent degradation of epithelial growth factor receptor. Moreover, the present study also revealed a preventive effect of HGF on atherosclerotic change in an Ang II infusion and cuff HGF transgenic mouse model.
These data suggest that the HGF/c-Met system might regulate extrinsic factor signaling that maintains the homeostasis of organs.
Circulation Research 09/2009; 105(7):667-75, 13 p following 675. · 9.49 Impact Factor
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Masaki Mori,
Hironori Nakagami, Nobutaka Koibuchi,
Koichi Miura,
Yoichi Takami,
Hiroshi Koriyama,
Hiroki Hayashi,
Hisataka Sabe,
Naoki Mochizuki,
Ryuichi Morishita,
Yasufumi Kaneda
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ABSTRACT: Epithelial-mesenchymal transition (EMT) confers destabilization of cell-cell adhesion and cell motility required for morphogenesis or cancer metastasis. Here we report that zyxin, a focal adhesion-associated LIM protein, is essential for actin reorganization for cell migration in TGF-beta1-induced EMT in normal murine mammary gland (NMuMG) cells. TGF-beta1 induced the relocation of zyxin from focal adhesions to actin fibers. In addition, TGF-beta1 up-regulated zyxin via a transcription factor, Twist1. Depletion of either zyxin or Twist1 abrogated the TGF-beta1-dependent EMT, including enhanced cell motility and actin reorganization, indicating the TGF-beta1-Twist1-zyxin signal for EMT. Both zyxin and Twist1 were predominantly expressed in the cardiac atrioventricular canal (AVC) that undergoes EMT during heart development. We further performed ex vivo AVC explant assay and revealed that zyxin was required for the reorganization of actin fibers and migration of the endocardial cells. Thus, zyxin reorganizes actin fibers and enhances cell motility in response to TGF-beta1, thereby regulating EMT.
Molecular biology of the cell 06/2009; 20(13):3115-24. · 5.98 Impact Factor
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ABSTRACT: Although both hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are potent angiogenic growth factors in animal models of ischemia, their characteristics are not the same in animal experiments and clinical trials. To elucidate the discrepancy between HGF and VEGF, we compared the effects of HGF and VEGF on endothelial progenitor cells under angiotensin II stimulation, which is a well-known risk factor for atherosclerosis. Here, we demonstrated that HGF, but not VEGF, attenuated angiotensin II-induced senescence of endothelial progenitor cells through a reduction of oxidative stress by inhibition of the phosphatidylinositol-3,4,5-triphosphate/rac1 pathway. Potent induction of neovascularization of endothelial progenitor cells by HGF, but not VEGF, under angiotensin II was also confirmed by in vivo experiments using several models, including HGF transgenic mice.
Hypertension 01/2009; 53(1):77-82. · 6.21 Impact Factor
