• Department of Cardiovascular Medicine

Department of
Cardiovascular Medicine
Outline and Research Objectives
In 1998 the Department of Internal Medicine at University of Tokyo hospital was reor-
ganized to the more functional units based on clinical specialties of diseased organs.
Cardiologists from 5 departments of Internal Medicine were unified to the Department of
Cardiovascular Medicine. We at quite an early phase introduced techniques of molecular
biology into the research field of cardiovascular medicine. As a result, we could report fol-
lowing important findings: 1) phenotypic modulation of cardiac or vascular specific proteins
occurs during cardiac hypertrophy or arteriosclerosis. 2) intracellular mechanisms on how
mechanical stress causes cardiac hypertrophy; 3) identification of novel genes expressed
during heart development; 4) development of animal models for cardiovascular diseases by
using genetic engineering techniques (i.e. knockout mice of endothelin-1 and KLF5 genes
provided new findings for the research of this field); 5) therapeutic angiogenesis for experi-
mental myocardial infarction by growth factors was originally introduced in this depart-
ment; 6) We are developing an electronic patient record system by which prognosis as well
as risk factors of cardiovascular disease can be statistically analyzed. From a research stand-
point, our interests range throughout all fields of cardiovascular medicine ranging from
molecular biology to clinical research including genomics. Importantly, our research inter-
ests are aimed at making possible new diagnostics and treatment of cardiovascular diseases.
Areas of interest are as follows:
1) Transcriptional regulation in cardiovascular pathogenesis
2) Risk factor analysis of cardiovascular disease
3) Pathogenic mechanisms of cardiac hypertrophy and heart failure
4) Immunological basis of myocarditis and dilated cardiomyopathy
5) MRI in cardiovascular diseases
6) Early diagnosis of ischemic heart disease using radionuclide testing
7) Aerobic threshold and cardiac rehabilitation
8) Anti-arrhythmia therapy using atrial remodeling
9) Mechanism of post-PTCA restenosis
10) Molecular mechanisms of reperfusion injury
11) Genetic polymorphisms in cardiovascular disease
12) Differentiation of smooth muscle cells
13) Cardiac development
14) Gene expression and regulation in cardiomyocytes
15) Mouse genetic models of cardiovascular diseases and vascular development
16) Nitric oxide and endothelial function
17) Gene therapy of heart failure using cardiac contractile proteins
18) Clinical application of vasoactive substances
Faculties and Students Past Research and Major Accomplishments
Professor and Chair Ryozo Nagai, MD, PhD (1999~)
Lecturer Yasunobu Hirata, MD, PhD 1) Transcriptional regulation of expression of
Minoru Ohno, MD, PhD genes related to cardiovascular diseases
Yoshinori Seko, MD, PhD We have been focusing our research on the role of
Associate ...............................14 transcriptional regulation of gene expression in the
Postdoctoral Fellow ..............11 cardiovascular system with a particular interest on
Graduate student ..................28 regulation of phenotypic modulation of smooth mus-
Research student.....................7 cle and cardiac cells. In 1980s and early 1990s, Nagai
Secretary .................................4 et al isolated and characterized three types of smooth
157
muscle myosin heavy chains and found that they are proliferate, contributing thereby to neointima forma-
differentially expressed during vascular development. tion. Our results will also suggest a novel strategy to
Nagai et al furthermore isolated a DNA-binding factor, prevent vascular diseases, targeting mobilization (A),
Krüppel-like factor 5 (KLF5), as a transcription factor circulation (B), homing (C), differentiation (D) and pro-
of the embryonic isoform of smooth muscle myosin liferation (E) of putative smooth muscle progenitor
heavy chain gene (SMemb), whose expression is cells (Figure 2).
induced in phenotypically modulated smooth muscle
cell and cardiac fibroblast. Recently, by developing 3) Establishment of clinical data management sys-
knockout mice of KLF5 gene, we have found that tem and its practical application to genetic epi-
KLF5 is an essential regulator of cardiovascular demiology in cardiovascular medicine
remodeling which occurs in response to various exter- We have established a clinical data analysis system
nal stresses (Figure 1). We have further found that dif- on network, which enrolls more than 2000 patients
ferential chemical modifications and protein-protein who underwent coronary angiography in our depart-
interactions regulate this family of factors. We are cur- ment. By using this system we can analyze the rela-
rently investigating whether low molecular weight tionship between the genetic polymorphisms and the
compounds that inhibit functions of KLF5 are clinical- clinical of cardiovascular diseases such as coronary
ly applicable as a new therapeutic drug against cardio- artery diseases (CAD) and ischemic stroke. We
vascular diseases. demonstrated that the alanine/valine (A/V) polymor-
phism in the gene of 5,10-methylenetetrahydrofolate
2) Differentiation of smooth muscle cells in vas- reductase (MTHFR) geneis a significant genetic risk
cular lesions factor for CAD and ischemic stroke. This genetic vari-
On the contrary to general assumption that neoin- ant is a more powerful predictor of atherosclerotic dis-
tima cells are derived from medial smooth muscle eases, when the plasma folate levels are relatively low.
cells, we found that bone marrow cells give rise to the
majority of smooth muscle cells that contribute to 4) Development of mouse genetic models of car-
arterial remodeling in models of post-angioplasty diovascular diseases
restenosis, graft vasculopathy and hyperlipidemia- Our research interests include the pathophysiolog-
induced atherosclerosis. Notably, we found purified ical assessment of cardiovascular diseases by mice
hematopoietic stem cells differentiated into smooth gene engineering approach. We have generated
muscle cells in vitro and in vivo. We proposed that knockout and transgenic mice of adrenomedullin,
among blood cells there may be progenitors of ADAMTS-1, endothelin-1 and KLF5. We analyzed the
smooth muscle cells, which attach to the injured role of these genes and found that their expression is
endothelia, differentiate into smooth muscle cells and essential for normal growth of mice.
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 Figure 3 summarizes our strategy for clinical application of basic research on cardiovascular disease.
tion of peripheral blood cells effectively differentiates
Current Research into smooth muscle cells. We are determining the cell
surface marker to isolate the putative bone marrow-
1) Transcription factor such as Krüppel-like fac- derived smooth muscle progenitor cells. Using bone
tors in pathogenic mechanisms. marrow transplantation mice, we are identifying the
Modulation of transcription factors may lead to a effects of hyperlipidemia and drugs on mobilization,
new therapeutic strategy for cardiovascular disease. homing, differentiation of the progenitor cells in vari-
Ongoing studies include using proteomics approaches ous models of vascular injury described above
to understand the diverse protein-protein interactions
and regulation of these Krüppel-like factors. We have 3) Establishment of clinical data management sys-
already identified a novel repressor protein among tem.
others. Another focus of research surrounds under- To overcome the difficulty of filing complicated
standing the transcriptional regulation of these clinical parameters for genetic association studies, we
Krüppel-like factors in the context of chromatin are accumulating clinical data and constructing our
which is necessary to understand how transcription original database system. For genetic analyses, writ-
occurs in humans. ten informed consent to participate was obtained
from all the in-patients in our department. DNA sam-
2) Bone marrow-derived vascular progenitor cells ples obtained from the participants have reached
(1) Identification of bone marrow fraction con- approximately one thousand. Using them, we ana-
tributing to atherosclerosis lyzed over 50 genetic polymorphisms implicated to be
To determine which fraction of bone marrow cells associated with atherosclerotic diseases. Among plen-
contribute to the pathogenesis of vascular diseases, ty of SNPs analyzed in our study, we showed the
we are reconstituting bone marrow of the lethally polymorphisms in the MMP-1 and MMP-3 promoters
irradiated recipient mice with the hematopoietic stem are associated with disease susceptibility to myocar-
cells from LacZ mouse and the mesenchymal stem dial infarction. Also, our database system supports
cells from GFP mouse. We are applying following vas- several ongoing clinical epidemiological studies such
cular injury models to bone marrow-reconstitution as J-CAD.
mice: mouse femoral injury model, heterotopic cardiac
transplantation model and atherosclerotic model. 4) Genetic engineering for analysis of the role of
(2) Characterization of bone marrow-derived endogenous protein
vascular progenitor cells We are analyzing the in vivo function of KLF5
By using cell sorter, we are identifying which frac- using knockout mice. In response to external stress,
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KLF5 knockout mice exhibited diminished levels of Ryozo Nagai (1999-2001)
arterial wall thickening, cardiac hypertrophy, intersti- Grant from the Ministry of Health, Labour and
tial fibrosis and that angiotensin II induced expres- Welfare
sion of KLF5, which in turn activated growth factor Research on elucidation of the molecular mecha-
expression. KLF5 thus appears to be a key element nisms of specific diseases
Ryozo Nagai (2000-2002)
linking external stress and cardiovascular remodeling.
Grant from the Ministry of Education, Culture,
Sports, Science and Technology
Future Prospects Development of a new prognostic evaluation system
and treatment for patients with cardiovascular dis-
1) Dissection of the pathogenic mechanisms whereby ease based on gene polymorphisms
the Krüppel-like factors are involved in cardiovas- Ryozo Nagai (2000-2002)
cular disease will allow us to understand the Grant from the Ministry of Health, Labor and
diverse mechanisms by which this family of fac- Welfare
tors are involved in transcriptional regulation. By Research on development of angiogenesis and vascu-
such, we envision that targeted drug design to lar protection treatment
modulate these factors in this context will enable Ryozo Nagai (2002-2006)
us to propose a new therapeutic approach to car- Grant from the Ministry of Education, Culture,
Sports, Science and Technology
diovascular disease (e.g. pin-point drug design).
Molecular mechanism and organ remodeling: gene
2) Using our database system we have followed all
transcription and cell-cell interaction in mesenchy-
the cases periodically, thus we can get prospective mal cells
clinical data such as major cardiovascular events
and responsiveness to treatment such as drugs and
percutaneous coronary intervention. In future, we Select Publications
will be able to obtain several evidences from our
database system and genetic analyses, resulting in Diversity of smooth muscle myosin heavy chain
clinical application of such evidences in prediction isoforms
or prevention of major cardiovascular diseases. 1. Nagai R, Larson DM, Periasamy M. Characterization
3) We have shown that KLF5 is a crucial determinant of a mammalian smooth muscle myosin heavy chain
of the cellular response to cardiovascular injury, cDNA and its expression in various smooth muscle
playing a key role in mediating cardiovascular types. Proc Natl Acad Sci USA 85: 1047-1051, 1988.
remodeling. We are now analyzing the effect of 2. Nagai R, Kuro-o M, Babij P, Periasamy M.
compounds, which could modulate KLF5 function Identification of two types of smooth muscle myosin
to control remodeling in atherosclerosis and heart heavy chain isoforms by cDNA cloning and
failure. immunoblot analysis. J Biol Chem 264: 9734-9737,
4) Our studies will show that bone marrow cells 1989.
3. Kuro-o M, Nagai R, Tsuchimochi H, Katoh H, Yazaki
including hematopoietic stem cells have the poten-
Y, Ohkubo A, Takaku F. Developmentally regulated
tial to give rise to vascular progenitor cells that
expression of vascular smooth muscle myosin heavy
home in the damaged vessels, differentiate into chain isoforms. J Biol Chem 264: 18272-18275, 1989.
smooth muscle cells, and proliferate thereby con- 4. Kuro-o M, Nagai R, Tsuchimochi H, Katoh H, Tsai R-
tributing to vascular remodeling. We expect that C, Yazaki Y, Ohkubo A, Takaku F. cDNA cloning of a
atherogenic factors such as hyperlipidemia, inflam- myosin heavy chain isoform in embryonic smooth
mation, cytokines, and smoking will facilitate the muscles and its expression during vascular develop-
kinetics of smooth muscle progenitors. Our find- ment and in arteriosclerosis. J Biol Chem 266: 3768-
ings will provide the basis for the development of 3773, 1991.
new diagnostic strategies to predict atherosclerosis 5. Kim H-S, Aikawa M, Kimura K, Kuro-o M, Nakahara
by quantifying the circulating progenitors. K, Suzuki T, Katoh H, Okamoto E, Yazaki Y, Nagai R.
Ductus arteriosus: advanced differentiation of
smooth muscle cells demonstrated by myosin heavy
Research Grants chain isoform expression in rabbits. Circulation 88:
1804-1810, 1993.
Ryozo Nagai (1997-2001)
6. Aikawa M, Nalla Sivam P, Kuro-o M, Kimura K,
Grant from the Organization for Pharmaceutical
Nakahara K, Takewaki S, Yamaguchi H, Yazaki Y,
Safety and Research
Periasamy M, Nagai R. Human smooth muscle
Role of Klotho gene and its clinical application in car-
myosin heavy chain isoforms as molecular markers
diovascular disease
for vascular development and atherosclerosis. Circ
Res 73: 1000-1012, 1993.
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7. Suzuki T, H-S Kim, Kurabayashi M, Hamada H, Fujii tribute to atherosclerosis. Nature Med. 7: 382-383,
H, Aikawa M, Watanabe M, Yazaki Y, Nagai R 2001.
Preferential differentiation of P19 mouse embryonal 9. Sata M, Saiura A, Kunisato A, Tojo A, Okada S,
carcinoma cells into smooth muscle cells: use of Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R.
retinoic acid and antisense against the central nerv- Hematopoietic stem cells differentiate into vascular
ous system-specific POU transcription factor Brn-2. cells that participate in the pathogenesis of athero-
Circ Res 78:395-404,1996. sclerosis. Nature Med. 8: 403-409, 2002.
Regulation of smooth muscle cell differentiation Identification and function of anti-aging gene
and cardiovascular remodeling klotho
1. Watanabe M, Sakomura Y, Kurabayashi M, Manabe 1. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H,
I, Aikawa M, Kuro-o M, Suzuki T, Yazaki Y, Nagai R Suga T, Utsugi T, Ohyama Y, Kurabayashi M,
Structure and characterization of the 5’-Flanking Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T,
Region of the mouse smooth muscle myosin heavy Nishikawa S, Nagai R, Nabeshima Y. Mutation of the
chain (SM1/2) gene. Circ Res 78: 978-989, 1996. mouse Klotho gene leads to a syndrome resembling
2. Manabe I, Kurabayashi M, Shimomura Y, Kuro-o M, ageing. Nature 390: 45-51, 1997.
Watanabe N, Watanabe M, Aikawa M, Suzuki T, 2. Saito Y, Yamagishi T, Nakamura T, Ohyama Y,
Yazaki Y, Nagai R Isolation of the embryonic form of Aizawa H, Suga T, Matsumura Y, Masuda H,
smooth muscle myosin heavy chain (SMemb/NMHC- Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R.
B) gene and characterization of its 5’-flanking region. Klotho protein protects against endothelial dysfunc-
Biochem Biophys Res Commun 239:598-605, 1997. tion. Biochem Biophys Res Commun 248: 324-329,
3. Watanabe N, Kurabayashi M, Shimomura Y, Kawai- 1998.
Kowase K, Hoshino Y, Manabe I, Watanabe M, 3. Aizawa H, Saito Y, Nakamura T, Inoue M, Imanari T,
Aikawa M, Kuro-o M, Suzuki T, Yazaki Y, Nagai R Ohyama Y, Matsumura Y, Masuda H, Oba S, Mise N,
BTEB2, a Krppel-like transcription factor, regulates Kimura K, Hasegawa A, Kurabayashi M, Kuro-o M,
expression of the SMemb/Nonmuscle myosin heavy Nabeshima Y, Nagai R. Downregulation of the klotho
chain B (SMemb/NMHC-B) gene Circ Res 85: 182- gene in the kidney under sustained circulatory stress
191, 1999. in rats. Biochem Biophys Res Commun 249: 865-871,
4. Kawai-Kowase K, Kurabayashi M, Hoshino Y, 1998.
Ohyama Y, Nagai R. Transcriptional activation of the 4. Suga T, Kurabayashi M, Sando Y, Ohyama Y, Maeno
zinc finger transcription factor BTEB2 gene by Egr-1 T, Maeno Y, Aizawa H, Matsumura Y, Kuwaki T,
through mitogen-activated protein kinase pathways Kuro-o M, Nabeshima Y, Nagai R. Disruption of the
in vascular smooth muscle cells Circ Res 85: 787-795, klotho gene causes pulmonary emphysema in mice:
1999. defect in maintenance of pulmonary integrity during
5. Hoshino Y, Kurabayashi M, Kanda T, Hasegawa A, postnatal life Am J Respir Cell Mol Biol 22: 26-33,
Sakamoto H, Okamoto Ei, Kowase K, Watanabe N, 2000.
Manabe I, Suzuki T, Nakano A, Takase Si, Wilcox 5. Nagai R, Saito Y, Ohyama Y, Aizawa H, Suga T,
JN, Nagai R. Regulated expression of the BTEB2 tran- Nakamura T, Kurabayashi M, Kuro-o M Endothelial
scription factor in vascular smooth muscle cells : dysfunction in the klotho mouse and downregula-
analysis of developmental and pathological expres- tion of klotho gene expression in various animal
sion profiles shows implications as a predictive fac- models of vascular and metabolic diseases. Cell Mol
tor for restenosis. Circulation 102: 2528-2534, 2000. Life Sci 57: 738-746, 2000.
6. Sekiguchi K, Kurabayashi M, Oyama Y, Aihara Y, 6. Saito Y, Nakamura T, Ohyama Y, Suzuki T, Iida A,
Tanaka T, Sakamoto H, Hoshino Y, Kanda T, Shiraki-Iida T, Kuro-o M, Nabeshima Y, Kurabayashi
Yokoyama T, Shimomura Y, Iijima H, Ohyama Y, M, Nagai R. In vivo klotho gene delivery protects
Nagai R. Homeobox protein hex induces SMemb/ against endothelial dysfunction in multiple risk fac-
Nonmuscle myosin heavy chain-B gene expression tor syndrome. Biochem Biophys Res Commun
through the cAMP-responsive element. Circ Res 88: 276:767-772, 2000.
52-28, 2001. 7. Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S,
7. Shindo T, Manabe I, Fukushima Y, Tobe K, Aizawa Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M,
K, Miyamoto S, Kawai-Kowase K, Moriyama N, Imai Nangaku M, Hirata Y, Nagai R. In vivo klotho gene
Y, Kawakami H, Nishimatsu H, Ishikawa T, Suzuki transfer ameliorates angiotensin II-induced renal
T, Morita H, Maemura K, Sata M, Hirata Y, Komukai damage. Hypertension. 39:838-843, 2002.
M, Kagechika H, Kadowaki T, Kurabayashi M, Nagai
R. Krppel-like zinc-finger transcription factor Intracellular signaling and transcription factors of
KLF5/BTEB2 is a target for angiotensin II signaling cardiac hypertrophy
and an essential regulator of cardiovascular remodel- 1. Kojima M, Shiojima I, Yamazaki T, Komuro I, Nagai
ing. Nature Med. 8:856-873, 2002. R, Yazaki Y. Angiotensin II receptor antagonist
8. Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. TCV116 regresses hypertensive left ventricular
Circulating smooth muscle progenitor cells con- hypertrophy in vivo and inhibits intracellular signal-
161
 ing pathway of stretch-mediated cardiomyocyte Nagai R, Yazaki Y, Nabeshima Y. Salt-sensitinve
hypertrophy in vitro. Circulation 89: 2204-2211, hypertension in transgenic mice overexpressing sodi-
1994 um-proton exchanger. Circ Res 76: 148-153, 1995.
2. Shimoyama M, Hayashi D, Takimoto E, Zou Y, Oka 3. Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada
T, Uozumi H, Kudoh S, Shibasaki F, Yazaki Y, Nagai T, Kurihara Y, Imai T, Wang Y, Ogata M, Nishimatsu
R, Komuro I. Calcineurin plays a critical role in pres- H, Moriyama N, Oh-hashi Y, Morita H, Ishikawa T,
sure overload-induced cardiac hypertrophy. Nagai R, Yazaki Y, Matsushima K. ADAMTS-1: a
Circulation. 100:2449-2454, 1999. metalloproteinase-disintegrin essential for normal
3. Zhu W, Zou Y, Aikawa R, Harada K, Kudoh S, growth, fertility, and organ morphology and func-
Uozumi H, Hayashi D, Gu Y, Yamazaki T, Nagai R, tion. J Clin Invest. 105:1345-1352, 2000.
Yazaki Y, Komuro I. MAPK superfamily plays an 4. Shindo T, Kurihara H, Maemura K, Kurihara Y,
important role in daunomycin-induced apoptosis of Kuwaki T, Izumida T, Minamino N, Ju KH, Morita H,
cardiac myocytes. Circulation. 100:2100-2107,1999. Oh-hashi Y, Kumada M, Kangawa K, Nagai R, Yazaki
4. Aikawa R, Nawano M, Gu Y, Katagiri H, Asano T, Y. Hypotension and resistance to lipopolysaccharide-
Zhu W, Nagai R, Komuro I. Insulin prevents car- induced shock in transgenic mice overexpressing
diomyocytes from oxidative stress-induced apoptosis adrenomedullin in their vasculature. Circulation.
through activation of PI3 kinase/Akt. Circulation. 101:2309-2316, 2000.
102: 2873-2879, 2000. 5. Shindo T, Kurihara Y, Nishimatsu H, Moriyama N,
5. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju
Nagai R, Komuro I. Tbx5 associates with Nkx2-5 and KH, Minamino N, Kangawa K, Ishikawa T, Fukuda
synergistically promotes cardiomyocyte differentia- M, Akimoto Y, Kawakami H, Imai T, Morita H,
tion. Nature Genet. 28:276-280, 2001. Yazaki Y, Nagai R, Hirata Y, Kurihara H. Vascular
6. Hosoda T, Monzen K, Hiroi Y, Oka T, Takimoto E, abnormalities and elevated blood pressure in mice
Yazaki Y, Nagai R, Komuro I. A novel myocyte-spe- lacking adrenomedullin gene. Circulation. 104:1964-
cific gene Midori promotes the differentiation of 1971, 2001.
P19CL6 cells into cardiomyocytes. J Biol Chem. 6. Morita H, Kurihara H, Yoshida S, Saito Y, Shindo T,
276:35978-35989, 2001. Oh-Hashi Y, Kurihara Y, Yazaki Y, Nagai R. Diet-
7. Uozumi H, Hiroi Y, Zou Y, Takimoto E, Toko H, Niu induced hyperhomocysteinemia exacerbates neointi-
P, Shimoyama M, Yazaki Y, Nagai R, Komuro I. ma formation in rat carotid arteries after balloon
gp130 plays a critical role in pressure overload- injury. Circulation. 103:133-139, 2001
induced cardiac hypertrophy. J Biol Chem. 276: 7. Yasuda SI, Sugiura S, Kobayakawa N, Fujita H,
23115-23119, 2001. Yamashita H, Katoh K, Saeki Y, Kaneko H, Suda Y,
8. Zou Y, Hiroi Y, Uozumi H, Takimoto E, Toko H, Zhu Nagai R, Sugi H. A novel method to study contrac-
W, Kudoh S, Mizukami M, Shimoyama M, Shibasaki tion characteristics of a single cardiac myocyte using
F, Nagai R, Yazaki Y, Komuro I. Calcineurin plays a carbon fibers. Am J Physiol Heart Circ Physiol.
critical role in the development of pressure overload- 281:H1442-6, 2001.
induced cardiac hypertrophy. Circulation. 104:97- 8. Ishizaka N, Aizawa T, Ohno M, Usui Si S, Mori I,
101, 2001. Tang SS, Ingelfinger JR, Kimura S, Nagai R.
9. Zou Y, Hiroi Y, Uozumi H, Takimoto E, Toko H, Zhu Regulation and localization of HSP70 and HSP25 in
W, Kudoh S, Mizukami M, Shimoyama M, Shibasaki the kidney of rats undergoing long-term administra-
F, Nagai R, Yazaki Y, Komuro I. Calcineurin plays a tion of angiotensin II. Hypertension. 39:122-128,
critical role in the development of pressure overload- 2002.
induced cardiac hypertrophy. Circulation. 104:97-
101, 2001. NO and intracellular signaling pathways
10. Takimoto E, Yao A, Toko H, Takano H, Shimoyama 1. Nagata D, Suzuki E, Nishimatsu H, Yoshizumi M,
M, Sonoda M, Wakimoto K, Takahashi T, Akazawa Mano T, Walsh K, Sata M, Kakoki M, Goto A, Omata
H, Mizukami M, Nagai T, Nagai R, Komuro I. Sodium M, Hirata Y. Cyclin A downregulation and p21(cip1)
calcium exchanger plays a key role in alteration of upregulation correlate with GATA- 6-induced growth
cardiac function in response to pressure overload. arrest in glomerular mesangial cells. Circ Res. 87:
FASEB J 16:373-378, 2002. 699-704, 2000.
2. Sata M, Kakoki M, Nagata D, Nishimatsu H, Suzuki
Cardiovascular pathophysiology E, Aoyagi T, Sugiura S, Kojima H, Nagano T,
1. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Kangawa K, Matsuo H, Omata M, Nagai R, Hirata Y.
Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Adrenomedullin and nitric oxide inhibit human
Kamada N, Jishage K, Ouchi Y, Azume S, Toyoda Y, endothelial cell apoptosis via a cyclic GMP-independ-
Ishikawa T, Kumada M, and Yazaki Y. Elevated ent mechanism. Hypertension. 36: 83-88, 2000.
blood pressure and craniofacial abnormalities in mice 3. Suzuki E, Nagata D, Yoshizumi M, Kakoki M, Goto
deficient in endothelin-1. Nature 368: 703-710, 1994. A, Omata M, Hirata Y. Reentry into the cell cycle of
2. Kuro-o M, Hanaoka K, Hiroi Y, Noguchi T, Fujimori contact-inhibited vascular endothelial cells by a
Y, Takewaki S, Hayasaka M, Katoh H, Miyagishi A, phosphatase inhibitor. Possible involvement of
162
 extracellular signal-regulated kinase and phos- Nagai R. A novel biochemical diagnostic method for
phatidylinositol 3-kinase. J Biol Chem. 275: 3637- aortic dissection - the results of a prospective study
3644, 2000 using an immunoassay of smooth muscle myosin
4. Nagata D, Suzuki E, Nishimatsu H, Satonaka H, Goto heavy chain. Circulation 93:1244-1249, 1996
A, Omata M, Hirata Y. Transcriptional activation of 2. Yokoyama I, Yonekura K, Ohtake T, Yang W, Shin
the cyclin D1 gene is mediated by multiple cis-ele- WS, Yamada N, Ohtomo K, Nagai R. Coronary
ments, including SP1 sites and a cAMP-responsive microangiopathy in type 2 diabetic patients: relation
element in vascular endothelial cells. J Biol Chem. to glycemic control, sex, and microvascular angina
276: 662-669, 2001. rather than to coronary artery disease. J Nucl Med
5. Nishimatsu H, Suzuki E, Nagata D, Moriyama N, 41: 978-985, 2000
Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo 3. Iwasaki T, Iwasaki T, Aihara Y, Kanda T, Oriuchi N,
H, Goto A, Kitamura T, Hirata Y. Adrenomedullin Endo K, Katoh H, Suzuki T, Nagai R.
induces endothelium-dependent vasorelaxation via Immunoscintigraphy of aortic dissection with
the phosphatidylinositol 3-kinase/Akt-dependent 99mTc-labeled murine anti-smooth muscle myosin
pathway in rat aorta.Circ Res. 89: 63-70, 2001. monoclonal antibody in rats. J Nucl Med 42: 130-
6. Nishimatsu H, Hirata Y, Shindo T, Kurihara H, 137, 2001
Kakoki M, Nagata D, Hayakawa H, Satonaka H, Sata 4. Yokoyama I, Yonekura K, Moritan T, Tateno M,
M, Tojo A, Suzuki E, Kangawa K, Matsuo H, Momose T, Ohtomo K, Inoue Y, Nagai R.
Kitamura T, Nagai R. Role of endogenous Troglitazone improves whole-body insulin resistance
adrenomedullin in the regulation of vascular tone and skeletal muscle glucose use in type II diabetic
and ischemic renal injury: studies on patients. J Nucl Med. 42:1005-1010, 2001.
transgenic/knockout mice of adrenomedullin gene.
Circ Res. 90: 657-663, 2002.
7. Suzuki N, Kojima H, Urano Y, Kikuchi K, Hirata Y,
Nagano T. Orthogonality of calcium concentration
and ability of 4,5- diaminofluorescein to detect NO. J
Biol Chem 277:47-49, 2002.
Genetics of cardiovascular disease
1. Tanaka T, Nagai R, Tomoike H, Takata S, Yano K,
Yabuta K, Haneda N, Nakano O, Shibata A,
Sawayama T, Kasai H, Yazaki Y, Nakamura Y. Four
novel KVLQT1 and four novel HERG mutations in
familial long QT syndrome. Circulation 95: 565-567,
1997.
2. Nakajima T, Furukawa T, Tanaka T, Katayama Y,
Nagai R, Nakamura Y, Hiraoka M. Novel mechanism
of HERG current suppression in LQT2 shift in volt-
age dependence of HERG inactivation. Circ Res
83:415-422, 1998.
3. Itoh T, Tanaka T, Nagai R, Kamiya T, Sawayama T,
Nakayama T, Tomoike H, Sakurada H, Yazaki Y,
Nakamura Y. Genomic organization and mutational
analysis of HERG, a gene responsible for familial long
QT syndrome. Hum Genet 102: 435-439, 1998
4. Itoh T, Tanaka T, Nagai R, Kikuchi K, Ogawa S,
Okada S, Yamagata S, Yano K, Yazaki Y, Nakamura
Y. Genomic organization and mutational analysis of
KVLQT1, a gene responsible for familial long QT
syndrome. Hum Genet 103: 290-294, 1998
5. Iwasa H, Itoh T, Nagai R, Nakamura Y, Tanaka T.
Twenty single nucleotide polymorphisms (SNPs) and
their allelic frequencies in four genes that are respon-
sible for familial long QT syndrome in the Japanese
population. J Hum Genet 45: 182-183, 2000
Diagnosis and imaging of cardiovascular disease
1. Suzuki T, Katoh H, Watanabe M, Kurabayashi M,
Hiramori K, Hori S, Nobuyoshi M, Tanaka H,
Kodama K, Sato H, Suzuki S, Tsuchio Y, Yazaki Y,
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 Department of
Gastroenterology
Department Objectives
The goal of our department is to accurately diagnose and give the best available treat-
ment to patients, and develop better modalities for the future.
To attain the goal, we perform clinical and basic research.
Outline
In 1998, our current Department of Gastroenterology was established through the reor-
ganization of the Divisions of Internal Medicine, and is in charge of busy clinical practices;
5,000 outpatients a month and 1,200 new admissions a year. The most frequent cause of
admission is hepatocellular carcinoma, 500 a year, followed by gastrointestinal tract disor-
ders 400, pancreatobiliary 180, and others 120.
Outline-Hepatology
Unlike other countries, the majority (more than 90%) of our patients with liver disease
are due to hepatitis virus infection. Therefore, better understanding of virus replication and
pathogenesis may eventually lead to the eradication of the virus and the cure of diseases.
We have developed unique ablation treatment for hepatocellular carcinoma (HCC), for
which many patients have visited our department (Fig. 1); we have had 1,600 cases, proba-
bly the largest series in the world as a single institute experience.
Outline -Gastroenterology
Gastric cancer is the commonest cause of death in Japan. Similar to HCC, there is now
enough evidence that bacterial infection, Helicobacter pylori, induces or is at least strongly
related to cancer development. Along with clinical expertise like en bloc resection of cancer
(Fig. 2), better understanding of gastric injury due the infection could reduce the most com-
mon cause of death in Japan.
Recent increase in the number of colonic cancer is so noticeable. We found that this is
mainly due to increase in right sided colon (cecum and ascending colon) cancer in elderly
patients. The better understanding of right sided as well as left sided colonic cancers may
prevent further increase in the colonic neoplasm in a country where people enjoy unprece-
dented length of life.
Outline -Pancreatobiliary
Pancreatic cancer with incredibly poor prognosis (average survival of 200 days) is insidi-
ously increasing in Japan. There is not even a clue for high risk group. We need, though dif-
ficult, to find out high risk groups and better treatment.
Fig 1. Percutaneous tumor ablation.
(A) During treatment: fine needle was inserted into the tumor.
(B) After treatment: the tumor was completely ablated
Fig 2. Endoscopic tumor resection.
(A) After injection of saline, the tumor was cut around.
(B) en bloc resection: the tumor was completely removed.
164
 HCC, we first revealed natural course of chronic hepa-
Faculties and Students titis to HCC ; this is by step-wise progression of hepat-
Professor and Chair Masao Omata, M.D., Ph.D. (from ic fibrosis (Ann Intern Med 2000;132:517-524). And
1992) eradication of virus by interferon could reduce the
Lecturer Takao Kawabe, M.D., Shin Onishi, incidence of HCC (Ann Intern Med 1999;131:174-181)
M.D. with resolution of hepatic fibrosis even in cirrhosis,
Associate ...............................19 previously thought irreversible (Ann Intern Med
Postgraduate Fellow ............33 2000;132:517-524). Furthermore, it was recently
Graduate Student..................23 revealed that overall mortality (not just HCC) was
Research Studen .............