Satoru Eguchi

Temple University, Filadelfia, Pennsylvania, United States

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Publications (143)717.11 Total impact

  • Steven J. Forrester · Satoru Eguchi ·

    Hypertension 11/2015; DOI:10.1161/HYPERTENSIONAHA.115.06532 · 6.48 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) activation impacts the physiology and pathophysiology of the cardiovascular system, and inhibition of EGFR activity is emerging as a potential therapeutic strategy to treat diseases including hypertension, cardiac hypertrophy, renal fibrosis, and abdominal aortic aneurysm. The capacity of G protein-coupled receptor (GPCR) agonists, such as angiotensin II (AngII), to promote EGFR signaling is called transactivation and is well described, yet delineating the molecular processes and functional relevance of this crosstalk has been challenging. Moreover, these critical findings are dispersed among many different fields. The aim of our review is to highlight recent advancements in defining the signaling cascades and downstream consequences of EGFR transactivation in the cardiovascular renal system. We also focus on studies that link EGFR transactivation to animal models of the disease, and we discuss potential therapeutic applications. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 56 is January 06, 2016. Please see for revised estimates.
    Annual Review of Pharmacology 11/2015; 56(1). DOI:10.1146/annurev-pharmtox-070115-095427 · 18.37 Impact Factor
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    ABSTRACT: Regulator of G protein signaling 2 (RGS2) controls G protein coupled receptor (GPCR) signaling by acting as a GTPase-activating protein for heterotrimeric G proteins. Certain Rgs2 gene mutations have been linked to human hypertension. Renal RGS2 deficiency is sufficient to cause hypertension in mice; however, the pathological mechanisms are unknown. Here we determined how the loss of RGS2 affects renal function. We examined renal hemodynamics and tubular function by monitoring renal blood flow (RBF), glomerular filtration rate (GFR), epithelial sodium channel (ENaC) expression and localization, and pressure natriuresis in wild type (WT) and RGS2 null (RGS2-/-) mice. Pressure natriuresis was determined by stepwise increases in renal perfusion pressure (RPP) and blood flow, or by systemic blockade of nitric oxide synthase with L-NG-Nitroarginine methyl ester (L-NAME). Baseline GFR was markedly decreased in RGS2-/- mice compared to WT controls (5.0 +/- 0.8 vs. 2.5 +/- 0.1 mul/min/g body weight, p<0.01). RBF was reduced (35.4 +/- 3.6 vs. 29.1 +/- 2.1 mul/min/g body weight, p=0.08) while renal vascular resistance (RVR; 2.1 +/- 0.2 vs. 3.0 +/- 0.2 mmHg/mul/min/g body weight, p<0.01) was elevated in RGS2-/- compared to WT mice. RGS2 deficiency caused decreased sensitivity and magnitude of changes in RVR and RBF after a step increase in RPP. The acute pressure-natriuresis curve was shifted rightward in RGS2-/- relative to WT mice. Sodium excretion rate following increased RPP by L-NAME was markedly decreased in RGS2-/- mice and accompanied by increased translocation of ENaC to the luminal wall. We conclude that RGS2 deficiency impairs renal function and autoregulation by increasing renal vascular resistance and reducing renal blood flow. These changes impair renal sodium handling by favoring sodium retention. The findings provide a new line of evidence for renal dysfunction as a primary cause of hypertension.
    PLoS ONE 07/2015; 10(7):e0132594. DOI:10.1371/journal.pone.0132594 · 3.23 Impact Factor
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    ABSTRACT: The concept of enhancing structural integrity of mitochondria has emerged as a novel therapeutic option for cardiovascular disease. Flow-induced increase in laminar shear stress is a potent physiological stimulant associated with exercise which exerts atheroprotective effects in the vasculature. However, the effect of laminar shear stress on mitochondrial remodeling within the vascular endothelium and its related functional consequences remain largely unknown. Using in vitro and in vivo complementary studies, here, we report that aerobic exercise alleviates the release of endothelial microparticles in pre-hypertensive individuals, and that these salutary effects are, in part, mediated by shear stress-induced mitochondrial biogenesis. Circulating levels of total (CD31(+)/CD42a(-)) and activated (CD62E(+)) microparticles released by endothelial cells were significantly decreased (~40% for both) after a 6 month supervised aerobic exercise training program in individuals with pre-hypertension. In cultured human endothelial cells, laminar shear stress reduced the release of endothelial microparticles, which was accompanied by an increase in mitochondrial biogenesis through a SIRT1-dependent mechanism. Resveratrol, a SIRT1 activator, treatment showed similar effects. SIRT1 knockdown using siRNA completely abolished the protective effect of shear stress. Disruption of mitochondrial integrity by either antimycin A or PGC-1α siRNA significantly increased the number of total, and activated, released endothelial microparticles, and shear stress restored these back to basal levels. Collectively, these data demonstrate a critical role of endothelial mitochondrial integrity in preserving endothelial homeostasis. Moreover, prolonged laminar shear stress, which is systemically elevated during aerobic exercise in the vessel wall, mitigates endothelial dysfunction by promoting mitochondrial biogenesis. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 05/2015; 309(3):ajpheart.00438.2014. DOI:10.1152/ajpheart.00438.2014 · 3.84 Impact Factor
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    ABSTRACT: The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.
    Hypertension 04/2015; 65(6). DOI:10.1161/HYPERTENSIONAHA.115.05344 · 6.48 Impact Factor
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    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; 128(9). DOI:10.1042/CS20140696 · 5.60 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; 64(3). DOI:10.2337/db14-0784 · 8.10 Impact Factor
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    Hypertension 09/2014; 64(Suppl 1):A428-A428. · 6.48 Impact Factor
  • Takashi Obama · Satoru Eguchi ·

    Journal of Molecular and Cellular Cardiology 07/2014; 75. DOI:10.1016/j.yjmcc.2014.07.004 · 4.66 Impact Factor
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    ABSTRACT: Background: 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. Methods: Cultured vascular smooth muscle cells were stimulated with 100 nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter-reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. Results: In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II-infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. Conclusions: Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α-dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system.
    American Journal of Hypertension 05/2014; 28(1). DOI:10.1093/ajh/hpu094 · 2.85 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; 184(7). DOI:10.1016/j.ajpath.2014.04.001 · 4.59 Impact Factor
  • Takashi Obama · Rosario Scalia · Satoru Eguchi ·

    Hypertension 04/2014; 63(6). DOI:10.1161/HYPERTENSIONAHA.114.03288 · 6.48 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; 127(1). DOI:10.1042/CS20140081 · 5.60 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; 306(8). DOI:10.1152/ajpcell.00131.2013 · 3.78 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; 126(11). DOI:10.1042/CS20130660 · 5.60 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; 62. DOI:10.1016/j.yjmcc.2013.05.005 · 4.66 Impact Factor
  • Akito Eguchi · Satoru Eguchi · Douglas G Tilley ·

    Hypertension 04/2013; 61(5). DOI:10.1161/HYPERTENSIONAHA.113.01184 · 6.48 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; 228(1). DOI:10.1016/j.atherosclerosis.2013.02.033 · 3.99 Impact Factor
  • Katherine J Elliott · Keita Kimura · Satoru Eguchi ·

    Hypertension 02/2013; 61(4). DOI:10.1161/HYPERTENSIONAHA.111.00943 · 6.48 Impact Factor

Publication Stats

7k Citations
717.11 Total Impact Points


  • 2004-2015
    • Temple University
      • Department of Physiology
      Filadelfia, Pennsylvania, United States
  • 2005-2013
    • Cardiovascular Research Foundation
      New York, New York, United States
  • 1996-2004
    • Vanderbilt University
      • Department of Biochemistry
      Нашвилл, Michigan, United States
  • 2003
    • Showa University
      • Institute of Molecular Oncology
      Shinagawa, Tōkyō, Japan
  • 2002
    • Yokohama City University
      Yokohama, Kanagawa, Japan
  • 1999-2002
    • Meharry Medical College
      Nashville, Tennessee, United States
  • 1991-2000
    • Tokyo Medical and Dental University
      • • Department of Molecular Endocrinology and Metabolism
      • • Department of Internal Medicine
      Edo, Tōkyō, Japan
  • 1990-1991
    • Tokyo Institute of Technology
      • Department of Biological Sciences
      Edo, Tōkyō, Japan