Satoru Eguchi

Temple University, Philadelphia, Pennsylvania, United States

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Publications (130)671.1 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin II has been implicated in the development of abdominal aortic aneurysm. In vascular smooth muscle cells, angiotensin II activates epidermal growth factor receptor (EGFR) mediating growth promotion. We hypothesized that inhibition of EGFR prevents angiotensin II-dependent abdominal aortic aneurysm. C57BL/6 mice were co-treated with angiotensin II and β-aminopropionitrile to induce abdominal aortic aneurysm with or without a treatment of EGFR inhibitor, erlotinib. Without erlotinib, 64.3% of mice were dead due to aortic rupture. All surviving mice had abdominal aortic aneurysm associated with EGFR activation. Erlotinib-treated mice did not die and developed far fewer abdominal aortic aneurysm. The maximum diameters of abdominal aortas were significantly shorter with erlotinib treatment. In contrast, both erlotinib-treated and non-treated mice developed hypertension. The erlotinib treatment of abdominal aorta was associated with lack of EGFR activation, endoplasmic reticulum stress, oxidative stress, interleukin-6 induction and matrix deposition. EGFR activation in abdominal aortic aneurysm was also observed in humans. In conclusion, EGFR inhibition appears to protect mice from abdominal aortic aneurysm formation induced by angiotensin II plus β-aminopropionitrile. The mechanism seems to involve suppression of vascular EGFR and endoplasmic reticulum stress.
    Clinical Science 12/2014; · 5.63 Impact Factor
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    ABSTRACT: Plasma homocysteine (Hcy) levels are positively correlated with cardiovascular mortality in diabetes. However, the joint effect of hyperhomocysteinemia (HHcy) and hyperglycemia (HG) on endothelial dysfunction (ED) and the underlying mechanisms have not been studied.Mild (22 µmol/L) and moderate HHcy (88 µmol/L) were induced in cystathionine β-synthase wild type (Cbs(+/+)) and heterozygous deficient (Cbs(-/+)) mice by a high methionine (HM) diet. HG was induced by consecutive injection of streptozotocin. We found that HG worsened HHcy and elevated Hcy levels to 55 µmol/L and 173 µmol/L in Cbs(+/+) and Cbs(-/+) mice fed a HM diet, respectively. Both mild and moderate HHcy aggravated HG-impaired endothelium-dependent vascular relaxation to acetylcholine, which was completely abolished by endothelial nitric oxide synthase (eNOS) inhibitor L-NAME. HHcy potentiated HG-induced calpain activation in aortic endothelial cells isolated from Cbs mice. Calpain inhibitors rescued HHcy- and HHcy/HG-induced ED in vivo and ex vivo. Moderate HHcy and HG-induced μ-calpain activation was potentiated by a combination of HHcy and HG in the mouse aorta. μ-calpain siRNA (μ-calpsiRNA) prevented HHcy/HG-induced ED in the mouse aorta and calpain activation in human aortic endothelial cells (HAECs) treated with DL-homocysteine (500 µmol/L) and D-glucose (25 mmol) for 48 hrs. In addition, HHcy accelerated HG-induced superoxide production as determined by DHE and 3-NT staining and urinary 8-isoprostane/creatinine assay. Antioxidants rescued HHcy/HG-induced ED in mouse aortas and calpain activation in cultured HAECs. Finally, HHcy potentiated HG-suppressed NO production and eNOS activity in HAECs, which were prevented by calpain inhibitors or μ-calpain siRNA. HHcy aggravated HG-increased phosphorylation of eNOS at threonine 497/495 in the mouse aorta and HAECs. HHcy/HG induced eNOSp-Thr497/495 was reversed by µ-calpsiRNA and adenoviral transduced dominant negative PKCβ2 in HAECs.HHcy and HG induced ED, which was potentiated by the combination of HHcy and HG via μ-calpain/PKCβ2 activation-induced eNOSp-Thr497/495 and eNOS inactivation.
    Diabetes 10/2014; · 7.90 Impact Factor
  • Takashi Obama, Satoru Eguchi
    Journal of Molecular and Cellular Cardiology 07/2014; · 5.22 Impact Factor
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    ABSTRACT: A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature.
    American Journal of Hypertension 05/2014; · 3.40 Impact Factor
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    ABSTRACT: We tested the hypothesis that IL-19, a putative member of the type 2 helper T-cell family of anti-inflammatory interleukins, can attenuate intimal hyperplasia and modulate the vascular smooth muscle cell (VSMC) response to injury. Ligated carotid artery of IL-19 knockout (KO) mice demonstrated a significantly higher neointima/intima ratio compared with wild-type (WT) mice (P = 0.04). More important, the increased neointima/intima ratio in the KO could be reversed, or rescued, by injection of 10 ng/g per day recombinant IL-19 into the KO mouse (P = 0.04). VSMCs explanted from IL-19 KO mice proliferated significantly more rapidly than WT. This could be inhibited by addition of IL-19 to KO VSMCs (P = 0.04 and P < 0.01). IL-19 KO VSMCs migrated more rapidly compared with WT (P < 0.01). Interestingly, there was no type 1 helper T-cell polarization in the KO mouse, but there was significantly greater leukocyte infiltrate in the ligated artery in these mice compared with WT. IL-19 KO VSMCs expressed significantly greater levels of inflammatory mRNA, including IL-1β, tumor necrosis factor α, and monocyte chemoattractant protein-1 in response to tumor necrosis factor α stimulation (P < 0.01 for all). KO VSMCs expressed greater adhesion molecule expression and adherence to monocytes. Together, these data indicate that IL-19 is a previously unrecognized counterregulatory factor for VSMCs, and its expression is an important protective mechanism in regulation of vascular restenosis.
    American Journal Of Pathology 05/2014; · 4.60 Impact Factor
  • Takashi Obama, Rosario Scalia, Satoru Eguchi
    Hypertension 04/2014; · 7.63 Impact Factor
  • Takashi Obama, Satoru Eguchi
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    ABSTRACT: Integrin-linked kinase predominantly localizes at focal adhesions to regulate actin cytoskeletal dynamics including cell migration and matrix remodeling. While recent studies suggest both physiological and pathophysiological roles of Integrin-linked kinase in the cardiovascular and renal system, its involvement in hypertensive organ dysfunctions such as those that occur in kidney had never been investigated. In this issue of Clinical Science, Alique M and co-workers have demonstrated that angiotensin II-induced renal inflammatory responses were attenuated in mice with conditional deficiency of Integrin-linked kinase, which were associated with suppression of nuclear factor-κB activation and reactive oxygen species generation but not hypertension. The significance, potential mechanisms and future direction will be presented and discussed in this commentary.
    Clinical Science 01/2014; · 5.63 Impact Factor
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    ABSTRACT: The existence of a local renin-angiotensin system (RAS) in neurons was first postulated forty years ago. Further studies indicated intraneuronal generation of angiotensin II (ANG II). However, the function and signaling mechanisms of intraneuronal ANG II remained elusive. Since angiotensin II type 1 receptor, AT1, is the major type of receptor mediating the effects of ANG II, we used intracellular microinjection and concurrent calcium and voltage imaging to examine the functionality of intracellular AT1 receptor in neurons. We show here that intracellular administration of ANG II produces a dose-dependent elevation in cytosolic Ca(2+) concentration, [Ca(2+)]i, in hypothalamic neurons, that is sensitive to AT1 receptor antagonism. Endo-lysosomal, but not Golgi apparatus disruption, prevents the effect of microinjected ANG II on [Ca(2+)]i. Additionally, the ANG II-induced Ca(2+) response is dependent on microautophagy and sensitive to inhibition of phospholipase C or antagonism of inositol 1,4,5-trisphosphate receptors. Furthermore, intracellular application of ANG II produces AT1-mediated depolarization of hypothalamic neurons, which was dependent on [Ca(2+)]i increase and on cation influx via transient receptor potential canonical channels. In summary, in the present study we provide evidence that intracellular ANG II activates endo-lysosomal AT1 receptors in hypothalamic neurons. Our results point to the functionality of a novel intraneuronal angiotensinergic pathway extending the current understanding of intracrine angiotensin II signaling.
    AJP Cell Physiology 01/2014; · 3.71 Impact Factor
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    ABSTRACT: Although angiotensin II (Ang II) and its receptor AT1 have been implicated in abdominal aortic aneurysm (AAA) formation, the proximal signaling events primarily responsible for AAA formation remain uncertain. Caveolae are cholesterol-rich membrane microdomains that serve as a signaling platform to facilitate the temporal and spatial localization of signal transduction events including those stimulated by Ang II. Caveolin-1 (Cav1) enriched caveolae in vascular smooth muscle cells mediate ADAM17-dependent epidermal growth factor receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Here, we have tested our hypothesis that Cav1 plays a critical role for development of AAA at least in part via its specific alteration of Ang II signaling within caveolae. Cav1-/- mice and the control wild-type mice were co-infused with Ang II and β-aminopropionitrile to induce AAA. We found that Cav1-/- mice with the co-infusion did not develop AAA compared to control mice in spite of hypertension. We found an increased expression of ADAM17 and enhanced phosphorylation of EGFR in AAA. These events were markedly attenuated in Cav1-/- aortae with the co-infusion. Furthermore, Cav1-/- mice aortae with the co-infusion showed less endoplasmic reticulum stress, oxidative stress and inflammatory responses compared to aortae from control mice. Cav1 silencing in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 appears to play a critical role in the formation of AAA and associated endoplasmic reticulum/oxidative stress presumably through the regulation of caveolae compartmentalized signals induced by Ang II.
    Clinical Science 12/2013; · 5.63 Impact Factor
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    ABSTRACT: Small interfering RNA (siRNA) mediated gene silencing has been utilized as a powerful molecular tool to study the functional significance of a specific protein. However, due to transient gene silencing and insufficient transfection efficiency, this approach can be problematic in primary cell culture such as vascular smooth muscle cells. To overcome this weakness, we utilized an adenoviral-encoded microRNA (miRNA)-embedded siRNA "mi/siRNA"-based RNA interference. Here, we report the results of silencing a disintegrin and metalloprotease 17 (ADAM17) in cultured rat vascular smooth muscle cells and its functional mechanism in angiotensin II signal transduction. 3 distinct mi/siRNA sequences targeting rat ADAM17 were inserted into pAd/CMV/V5-DEST and adenoviral solutions were obtained. Nearly 90% silencing of ADAM17 was achieved when vascular smooth muscle cells were infected with 100 multiplicity of infection of each ADAM17 mi/siRNA encoding adenovirus for 3 days. mi/siRNA-ADAM17 but not mi/siRNA-control inhibited angiotensin II-induced epidermal growth factor receptor trans-activation and subsequent extracellular signal-regulated kinase activation and hypertrophic response in the cells. mi/siRNA-ADAM17 also inhibited angiotensin II-induced heparin-binding epidermal growth factor-like factor shedding. This inhibition was rescued with co-infection of adenovirus encoding mouse ADAM17 but not by its cytosolic domain deletion mutant or cytosolic Y702F mutant. As expected, angiotensin II induced tyrosine phosphorylation of ADAM17 in the cells. In conclusion, ADAM17 activation via its tyrosine phosphorylation contributes to heparin-binding epidermal growth factor-like factor shedding and subsequent growth promoting signals induced by angiotensin II in vascular smooth muscle cells. An artificial mi/siRNA-based adenoviral approach appears to be a reliable gene-silencing strategy for signal transduction research in primary cultured vascular cells.
    Journal of Molecular and Cellular Cardiology 05/2013; · 5.15 Impact Factor
  • Akito Eguchi, Satoru Eguchi, Douglas G Tilley
    Hypertension 04/2013; · 7.63 Impact Factor
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    ABSTRACT: OBJECTIVE: The Max-interacting protein Mnt is a transcriptional repressor that can antagonize the transcriptional and proliferation-related activities of Myc. Here, we tested the hypothesis that Mnt is a negative regulator of pathological vascular remodeling. METHODS: Adenovirus encoding Mnt or control GFP was infected to cultured rat vascular smooth muscle cells (VSMC) and carotid arteries after a balloon angioplasty. RESULTS: In VSMC, adenoviral gene transfer of Mnt suppressed angiotensin II-induced protein expression of early growth response protein-1 (Egr1) and its promoter activation. Mnt adenovirus did not interfere with upstream signaling of angiotensin II. Angiotensin II-induced protein accumulation in VSMC was inhibited by Mnt adenovirus. Mnt adenovirus also inhibited platelet-derived growth factor-induced VSMC proliferation. Moreover, Mnt adenovirus prevented neointima formation in response to arterial injury. The adenoviral Mnt gene transfer also prevented Egr1 induction in neointima. CONCLUSION: These data identify Mnt as a previously unrecognized negative regulator of pathological vascular remodeling.
    Atherosclerosis 03/2013; · 3.71 Impact Factor
  • Hypertension 02/2013; · 7.63 Impact Factor
  • Tomonori Kobayashi, Satoru Eguchi
    Hypertension 06/2012; 60(1):20-1. · 7.63 Impact Factor
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    ABSTRACT: To fill the gap between acute and chronic stimulation methods of angiotensin II (Ang II) and obtain relevant signaling information, we have made an adenovirus vector encoding a furin-cleavable Ang II fusion protein. Vascular smooth muscle cells (VSMCs) were infected with adenovirus to evaluate Ang II production. Also, expression of early growth response-1 (Egr-1) and hypertrophic responses were examined in VSMCs. Acute stimulation of VSMCs with synthetic Ang II showed the peptide had a half-life of less than 1 h. Infection of VSMCs with Ang II adenovirus showed a time-dependent production of Ang II as early as 2 days and up to 7 days postinfection. The Ang II adenovirus induced VSMC hypertrophy, stimulated Egr-1 expression, and suppressed Ang II type 1 receptor mRNA expression. Chronic Ang II infusion in mice for 2 weeks markedly enhanced Egr-1 immunostaining in carotid artery compared with the control saline infusion. Application of the Ang II adenovirus vector to cultured cells will be useful to elucidate molecular and signaling mechanisms of cardiovascular diseases associated with enhanced Ang II production.
    American Journal of Hypertension 11/2011; 25(3):280-3. · 3.67 Impact Factor
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    ABSTRACT: The roles of rho-kinase (ROCK) and epidermal growth factor receptor (EGFR) were studied using an angiotensin II (AngII)-dependent hypertension rat model. Male Wistar rats were infused with AngII at a rate of 400 ng/kg body weight (BW)/min for 14 days. Effects of ROCK inhibitor, fasudil (20 mg/kg BW), and EGFR inhibitor, gefitinib (3 mg/kg BW), were studied. AngII infusion increased blood pressure (BP; 220 ± 19 mmHg) as well as the number of proliferating cells in glomeruli judged by Ki67 and proliferating cell nuclear antigen immunostaining and urinary protein excretion (118 ± 19 mg/day). AngII also decreased p27 expression and increased cyclin D1 expression in glomeruli, as well as induced dissociation of the nephrin- and podocin-immunostaining patterns in podocytes. Treatment with fasudil or gefitinib completely inhibited glomerular cell proliferation without changing the BP. Although the decreased p27 expression was reversed by both treatments, cyclin D1 induction was abolished only by gefitinib. Fasudil significantly reduced proteinuria (57.2 ± 17.5 mg/day), but not gefitinib (133.3 ± 30.9 mg/day). The dissociation of podocin and nephrin was ameliorated by fasudil, but not by gefitinib. ROCK and EGFR have distinct roles in proteinuria and glomerular cell proliferation in this model.
    Renal Failure 11/2011; 33(10):1005-12. · 0.94 Impact Factor
  • Allison M Bourne, Satoru Eguchi
    American Journal of Hypertension 10/2011; 24(10):1057-8. · 3.67 Impact Factor
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    Takehiko Takayanagi, Satoru Eguchi
    Hypertension 09/2011; 58(3):354-5. · 7.63 Impact Factor
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    ABSTRACT: A metalloprotease, ADAM17, mediates the generation of mature ligands for the epidermal growth factor receptor (EGFR). This is the key signaling step by which angiotensin II (AngII) induces EGFR transactivation leading to hypertrophy and migration of vascular smooth muscle cells (VSMCs). However, the regulatory mechanism of ADAM17 activity remains largely unclear. Here we hypothesized that caveolin-1 (Cav1), the major structural protein of a caveolae, a membrane microdomain, is involved in the regulation of ADAM17. In cultured VSMCs, infection of adenovirus encoding Cav1 markedly inhibited AngII-induced EGFR ligand shedding, EGFR transactivation, ERK activation, hypertrophy and migration, but not intracellular Ca(2+) elevation. Methyl-β-cyclodextrin and filipin, reagents that disrupt raft structure, both stimulated an EGFR ligand shedding and EGFR transactivation in VSMCs. In addition, non-detergent sucrose gradient membrane fractionations revealed that ADAM17 cofractionated with Cav1 in lipid rafts. These results suggest that lipid rafts and perhaps caveolae provide a negative regulatory environment for EGFR transactivation linked to vascular remodeling induced by AngII. These novel findings may provide important information to target cardiovascular diseases under the enhanced renin angiotensin system.
    Journal of Molecular and Cellular Cardiology 03/2011; 50(3):545-51. · 5.15 Impact Factor
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    ABSTRACT: The requirement of a metalloprotease, a disintegrin and metalloprotease 17 (ADAM17) for the growth of cultured vascular smooth muscle cells has been demonstrated in vitro. However, whether this metalloprotease is responsible for vascular remodeling in vivo remains unanswered. Rat carotid arteries were analyzed 2 weeks after a balloon angioplasty. The neointimal cells were strongly positive for ADAM17 immunostaining. Marked inhibition of intimal hyperplasia was observed in a dominant-negative ADAM17 adenovirus-treated carotid artery. Proliferating cell nuclear antigen-positive cells and phospho-epidermal growth factor receptor-positive cells in the neointima were reduced by dominant-negative ADAM17 as well. In contrast, the neointima formation, proliferating cell nuclear antigen-positive cells, and phospho-epidermal growth factor receptor-positive cells were markedly enhanced by wild-type ADAM17 adenovirus. In conclusion, ADAM17 activation is involved in epidermal growth factor receptor activation and subsequent neointimal hyperplasia after vascular injury. ADAM17 could be a novel therapeutic target for pathophysiological vascular remodeling.
    Hypertension 02/2011; 57(4):841-5. · 7.63 Impact Factor

Publication Stats

5k Citations
671.10 Total Impact Points

Institutions

  • 2004–2014
    • Temple University
      • • Department of Physiology
      • • Independence Blue Cross Cardiovascular Research Center (CVRC)
      Philadelphia, Pennsylvania, United States
  • 2011
    • Wakayama Medical University
      • Department of Internal Medicine
      Wakayama, Wakayama, Japan
  • 1999–2007
    • Meharry Medical College
      • Department of Physiology
      Nashville, Tennessee, United States
  • 1996–2005
    • Vanderbilt University
      • Department of Biochemistry
      Nashville, MI, United States
  • 2003
    • Showa University
      • Institute of Molecular Oncology
      Shinagawa, Tōkyō, Japan
  • 2002
    • Yokohama City University
      Yokohama, Kanagawa, Japan
  • 1991–2000
    • Tokyo Medical and Dental University
      • • Department of Molecular Endocrinology and Metabolism
      • • Department of Internal Medicine
      • • Department of Medicine II
      Edo, Tōkyō, Japan
  • 1990–1991
    • Tokyo Institute of Technology
      • Department of Biological Sciences
      Edo, Tōkyō, Japan