Department ofOrgan Pathophysiology andInternal Medicine
Health Service Center
Outline and Research Objectives
In 1972, Health Service Center was founded under the auspices of the Ministry of
Education and Culture to keep sound physical and mental environment in the University ofTokyo. The director of the Center has been elected from a member of Professors in Facultyof Medicine and dealt with two main services, 1) Primary care for undergraduate, graduate
and postgraduate students as well as Faculty Staff and 2) Health Control strategy. At the
opening of the Center, the main task was restricted to the Student with infectious disease
including tuberculosis and malnutrition and medical check of all students in several aspects.
The Center has three branch offices, in Hongo, Komaba and Kashiwa Campuses from 2001.
Recently, the number of students in the University is enormously increasing and reachedabout 25,000. The University also contains Faculty Staffs about 5,000. Target diseases
include a wide variety of sickness, ranging from acute but minor problems like common
cold, acute gastroenteritis, several accidents during experiment, injuries in sports, insomnia
or neurosis to grave or life-threatening sickness such as malignant neoplasms, AIDS,
Hepatitis C, imported infections from foreign countries, DMI and suicide. Graduate andPostgraduate Students are actually main human resources to produce the Research output inLaboratory. Their burdened life in both hard works to do until midnight and competitive
stress to reach a top-level scientist would cause several serious problems.
Official duties of the Center contain 1) Routine medical care of several problems, 2)
Health Check after entrance exam, 3) Regular Health check of all Faculty Members, 4)Regular Health Check for Students from Abroad, 5) Medical Education Programming forchronic diseases, 6) Regular Health Check for Students and Faculty Members treating hazardous materials or radioisotopes, 7) Issue of Health Check Forms, 8) Health Consultation in
general, 9) Health Check for the candidates of new staffs and so on.

Faculties and Students
Professor and Chair Teruhiko TOYO-OKA, M.D., Ph.D. (1991-)
Associate Professors Yoshio UEHRA, M.D., Ph.D. (1999-)
Tsukasa SASAKI, M.D., Ph.D. (2000-)
Lecturers
Shu UWATOKO, M.D., Ph.D. (1997-)
Jun-ichi SUZUKI, M.D., Ph.D. (1998-)
Takashi ISHIKAWA, M.D., Ph.D. (1998-)
Katsuyuki ANDO, M.D., Ph.D. (1997-)
Miyuki SADAMATSU, M.D., Ph.D. (2000-)
Hisako HIKIJI, M.D., Ph.D. (2001-)
Associates ...............................8

Past Research and Major Accomplishments
From 1976, the author has addressed to the pathophysiology of the most serious and popular problems
in medicine in Japan, heart failure. Precise mechanismof the development is still unknown on advanced

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heart failure from pressure overload secondary tohypertension, several kinds of valvular stenosis, volume overload due to congenital heart anomaly or
valvular insufficiency or from unidentified etiology
including idiopathic cardiomyopathy. Based on an
exact diagnosis, the treatment should be performed,
considering the clinical setting of the patients.
After finishing Ph.D. course in the laboratory ofProf. Setsuro EBASI, who is one of the most outstanding scientists in muscle biology, Dr. Tomoh MASAKI
and I have purified calcium- activated neutral protease(CANP or calpain) from cardiac muscle for the firsttime and characterized both the biochemical andpathological features. Studies on calpain continued
when I moved to the Department of Cardiology in
San Diego or Physiologisches Institut in Heidelberg
where calpain was found to be involved in the loss ofmyofibrillar proteins in myocardial infarction orplatelet aggregation.

Using in vivo 1H and 31P-NMR, the author has indicated structure abnormalities of sarcolemma as thecause for dilated cardiomyopathy (DCM) that is still
the most grave and incurable heart failure. The hereditary form of DCM due to gene abnormalities of cardiac actin, dystrophin, several sarcoglycans (SG) anddesmin has been reported in human cases. We havediscovered gene deletion of δ-SG in human and hamster with hereditary DCM and identified its breakpoint (Sakamoto et al., Proc.Natl.Acad.Sci.USA 1997;
Tsubata et al., J.Clin.Invest. 2000). Comparing withnormal control, BIO 14.6 strains that develop DCM
following a hypertrophy phase, some, but not all, SGs
except δ-SG remained. On the other hand, TO-2
strains, which develop DCM from an early stage, did
not express any SG at all (Kawada et. al., FEBS Lett.
1999). These results indicate the scheme that the
integrity of cell membrane is normally preserved
when all SG are present, but as demonstrated with
BIO 14.6 hamsters, develops compensatory hypertrophy when SG is partially present, and finally reaches
advanced heart failure, when all SGs were lost.
Results from northern blot analysis confirmed abundant mRNA expression of α−, β−, and γ-SGs, andtheir promoter structures were preserved.
Accordingly, we concluded that the actual cause of
DCM is the gene mutation of δ-SG and loss of otherSGs were originated from post-translational level.
To modulate translation of specific mRNA to protein, we demonstrated that transgene expression ismost effectively inhibited with CMV promoter-activated antisense DNA plasmid, rather than general antisense DNA (Chen et al., J.Biol.Chem. 2000; Wang etal., Circ.Res., 2001). In addition, with approval of ethical committee, we conducted genetic diagnosis of
mitochondrial cardiomyopathy and identified a novel
DCM-linked D-loop (Shin et al., Am.J.Hum.Genet.,
2000).
Since the discovery of dystrophin, heart failure
due to dystrophin-related proteins (DRP) abnormalities have been regarded as accompanying symptomsof congenital muscular dystrophy. Although there wasa report on proteolysis of dystrophin following viral
myocarditis, we have reported most cases of acquired
DRP disruption observed in chronic heart failure models were caused by the direct degradation of DRP complex including catecholamine toxicity and heart failure of the old myocardial infarction.
To develop gene therapy of advanced heart failure,
we employed several vectors. Using proteoliposome,
we have transfected eNOS gene to cardiac muscles invivo, and succeeded initiating apoptosis (Kawaguchi
et al., Circulation 1997). We have also indicated thenecessity to employ other vectors for the efficient,
long-term, and biologically inert transfection (Kawada
et al., BBRC, 1999). Our attempt to transduce thecausative gene when it is identified has shown that
responsible gene does improve pathophysiology andrescue the hereditary DCM (Kawada et al., PNAS
2002).

Current Research
Although the prognosis of advanced heart failure
typified by DCM is now gradually improving throughvarious pharmaceutical agents, the final choice isheart transplantation. However, there are still many
ethical, social and medical obstacles such as keeping
the number of donor hearts, and continuing immunosuppressant therapy after the transplantation duringwhole life. The development of gene therapy is anticipated as an ideal method to overcome these problems. As a solution for these problems, we proposed
the following 3-year-plan to develop new strategy forthe prevention and treatment of advanced heart failure (2002 to 2004).
• Research and Survey Projects in the Ministry of
Welfare to investigate the patient population of
the mutated gene previously cloned (2002).
• Development of new potential gene-delivery
system. Using safe and long-lasting adenoassociated virus (rAAV) as a vector, we previouslytransferred responsible gene with normal
sequence, via thoracotomy to above animal model,
which improved the prognosis. To examine if thismethod is clinically applicable to larger subhumananimals, as a step towards clinical use of the basic
research, we will conduct preclinical studies onmonkeys (2002-2004). Specifically, after initiatinglarge-scale production of rAAV (2002), and simultaneously develop administration methods withhigh transfection efficiency. (2003)• Search for more realistic gene-delivery route.
Clinical situation of the patients with advanced
heart failure, however, requires less aggressiveroute not under open chest surgery. Anotheradministration route via transcoronary route
might be preferable to attain the efficient and safedelivery (2004).
• Strict evaluation of safety in regards to generalpathology, immunology, and germ-line cell
infection. Trail of the rAAV administration toskeletal muscle cells is similar but more easilytransfectable than myocardial cells (2002-2003).
• Creation of advanced heart failure presenting
human-type DCM in larger animals. Small animal model does not always represent human diseases. Rhesus monkeys will be employed, because
the Ministry of Welfare in Japan has accepted thisspecies in a preclinical study (2003). Animal models of human-like DCM will be highly innovative
for the development of various disease treatments.

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• Cell transplantation combined with the genetherapy. Patients seek treatment only when
symptoms become severe. Gene therapy waseffective to prevent the disease progression but
could not regenerate the normal cells.
Transduction of normal sequence transgene to cultured muscle cells and create normalized cells in
vitro might be promising for the patients after the
onset of the symptoms. Fortunately, skeletal
myoblasts can proliferate and be transplantable tocardiac tissue and show new development of cardiac muscle cells. Transplantation of geneticallynormalized myoblasts will be promising for the
next generation gene therapy.

Future Prospects
Present project consists of two sections, as follows.
• Double vector strategy for the development ofknockout heart and novel therapy with monkeys. Previous report that knockout of δ-SG genein mice caused not only DCM but also coronary
spasm (Coral-Vasquez et al., Cell 1999). The contribution of myocardial ischemia is of great significance for the pathogenesis of DCM, although they
did not show clear evidence to support thescheme. Because of the limitation of handling insmall heart, no group has succeeded in the verification of the microvessel spasm. To clarify thecontribution of coronary spasm, we are trying toprepare not transgenic mice but knockout heart inlarge animals like Rhesus, to make it possible tovisualize coronary spasm by coronary angiogrrraphy and anaerobic metabolism as follows. AAV
consists of 5 subtypes, Serotype I to V.
Preliminary experiment showed that type V was
the most efficiently transfected both skeletal andcardiac muscle cells in vivo, followed by type III
and II. We have been verifying in vivo since lastyear and succeed in modifying the rAAVs for gene
vector. The rAAV type II as gene therapy vector,
known to be safe and to possess a long expression
period. In addition to type II, we have already prepared type V and are now making sure the safety.
(2002).
Since the serotype of these rAAV vectors completely differ, mutual interference does not take place.
This difference of serotypes has crucial meaning toour study. By applying different rAAV vectors at theinitial and secondary administration, different antigenicity does not prevent double transfection. In ourpresent study, we will initially administer rAAV type
V that is the most efficient with δ-SG antisense,
extensively to monkey cardiac muscle in vivo, andcreate a cardiospecific δ-SG deficient heart. Following

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validation of transfection via myocardial biopsy using
specific antibody to δ-SG, the pathogenesis will be
precisely examined whether they develop human-likeDCM (2003).
Subsequently, expression of δ-SG containing normal or abnormal sequence can be examined, usingrAAV type II. With the former gene, the rescue will be
expected, as demonstrated previously with hamsters.
With the latter animals, we will confirm the presenceof transgene, and examine the persistence of clinicalsymptoms of dilated cardiomyopathy by physiologicalexaminations by hemodynamics, echocardiography
and assay of BNP (2004).
• Combination therapy of gene and cell therapy at
the advanced heart failure.
Cell therapy will be promising for the treatment ofadvanced heart failure after progression to the degenerative process of cardiomyocytes. Simple cell transplantation tried in humans is not applicable to thecase with gene-deletion or mutation, because intrinsic
gene mutation universally occurs in all tissues including cardiac muscle and skeletal muscle. After skeletal
myoblasts in culture were proliferated and transfectedby normal gene, the treated and normalized muscle
cells can be transplanted to DCM heart. For ethicalconsiderations, genetic diagnosis a priori is essential
for identifying responsible gene or at least, actually
aggravating factor and for developing gene therapy. In
accordance with recommendations by Helsinki
Declaration, Science Council, Ministry of Education,
Ministry of Health and Welfare and related 8
Academic Societies, we requested for a strict inquisition by ethical committee. As stated above, we havealready demonstrated serious consideration to privacy
protection in our previous study on nation-wide
genetic diagnosis survey for the prevention of sudden
death and obtained very meaningful results (Shin etal., Am.J.Hum.Genet. 2000).

Research Grants from 1998 to 2002.
1998-2000 The Ministry of Education, Culture,
Science and Sports; Section A (1), “Novel gene therapyof dilated cardiomyopathy secondary to disruption ofdystrophin-related proteins”.
1998-2000 The Ministry of Education, Culture,
Science and Sports; Section A (2), “Prevention trial of
sudden death with using gene-based presymptomatic
diagnosis”.
2001 Uehara Memorial Foundation, “Developmentof gene-based therapy for dilated cardiomyopathy”.
2002-4 The Ministry of Education, Science, Culture
and Sports; Section A (1), “Gene or cell-engineered
therapy of advanced heart failure”.
2002-4 The Ministry of Health, Labor and Welfare;Translational Research Project from Basic Medicine toClinical Therapy, “Clinical application of gene therapy
with cell engineering for the treatment of advanced
heart failure”.

Select Publications
1. Ebashi S, Nonomura Y, Toyo-oka T. and Katayama E.
Regulation of muscle contraction by the calcium-troponin-tropomyosin system. Cambridge University
Press, Symposia of the Society for Experimental
Biology 30, 349-360, 1976.
2. Toyo-oka T, Shimizu T. and Masaki T. Inhibition ofproteolytic activity of calcium activated neutral proteasebyleupeptin
andantipain.
Biochem.Biophys.Res.Commun. 82, 484-491, 1978.
3. Toyo-oka T. Increased activity of intramuscular proteases in the hyperthyroid state. F.E.B.S.Lett. 117,
122-124, 1980.
4. Toyo-oka T. Calcium ion-insensitive contraction ofglycerinated porcine cardiac muscle fibers by Mg-inosine triphosphate. Circ.Res. 49, 1350-1355, 1981.
5. Toyo-oka T. and Ross JJ. Ca2+ sensitivity change andtroponin loss in cardiac natural actomyosin after
coronary occlusion. Am.J.Physiol. 240, H704-H708,
1981.
6. Toyo-oka T. Phosphorylation with cyclic adenosine 3’
5’ monophosphate-dependent protein kinase renders
bovine cardiac troponin sensitive to the degradationbycalcium-activatedneutralprotease.
Biochem.Biophys.Res.Commun. 107, 44-50, 1982.
7. Toyo-oka T, Nagayama K, Umeda M, Eguchi K. and
Hosoda S. Rhythmic change of myocardial phosphatemetabolite content in cardiac cycle observed bydepth-selected and EKG-gated in vivo 31P-NMR spectroscopy
in
a
whole
animal.
Biochem.Biophys.Res.Commun. 135, 808-815, 1986.
8. Ikeda U, Toyo-oka T. and Hosoda S. Identification of
two new calcium dependent hydrolases in thehuman heart. Biochem.Biophys.Res.Commun. 136,
773-777, 1986.
9. Toyo-oka T, Nagayama K, Umeda M, Ogawa S, Eguchi
K, Hosoda S. and Sugimoto T. Combined study of 1Hmagnetic resonance imaging and depth-selected,
EKG-gated 31P-magnetic resonance spectroscopy ofthe heart in vivo. Biochem.Biophys.Res.Commun.
144, 841-848, 1987.
10. Toyosaki N, Toyo-oka T, Natsume T, Katsuki T,
Tateishi T, Yaginuma T. and Hosoda S. Combination
therapy with diltiazem and nifedipine in patientswith effort angina pectoris. Circulation 77, 13701375, 1988.
11. Toyo-oka T. A critical review of NMR imaging andspectroscopy for the evaluation of cardiac hypertrophy in humans and experimental animals.
J.Mol.Cell.Cardiol. 5, 141-147, 1989.
12. Toyo-oka T, Arisaka H, Sanma H, Shin WS, Dan Y.
and Sugimoto T. Synergistic deleterious effect of
micromolar Ca ions and free radicals on respiratory
function of heart mitochondria at cytochrome C andits salvage trial. Biochem.Biophys.Res.Commun. 163,1397-1403, 1989.
13. Toyo-oka T, Arisaka H, Takayasu T, Tezuka T. and
Hosoda S. In vivo 31P-NMR spectroscopy of heart inhypoxia and identification of biochemical factors
responsible for contractility loss. Prog.Clin.Biol.Res.
315, 567-579, 1989.
14. Toyo-oka T, Shin WS, Okai Y, Dan Y, Morita M,
Iizuka M. and Sugimoto T. Collagen-stimulated
human platelet aggregation is mediated by endogenous calcium-activated neutral protease. Circ.Res. 64,
407-410, 1989.
15. Takayasu T, Toyo-oka T. and Hosoda S. Waste of
ATP for tension development in myocardial acidosis:
Chemomechanical uncoupling at myofibrillar level.
J.Mol.Cell.Cardiol. 22, 127-130, 1990.
16. Naitoh T, Toyo-oka T. and Sugimoto T. An endogenous Ca2+ channel agonist, endothelin-1, does notdirectly activate partially purified dihydropyridinesensitive Ca2+channel from cardiac muscle in a reconstituted system. Biochem.Biophys.Res.Commun. 171,1205-1210, 1990.
17. Okai-Matsuo Y, Takano-Ohmuro H, Toyo-oka T. and
Sugimoto T. A novel myosin heavy chain isoform invascular smooth muscle. Biochem. Biophys. Res.
Commun. 176, 1365-1370, 1991.
18. Shin WS, Toyo-oka T, Masuo M, Okai Y, Fujita H.
and Sugimoto T. Subpopulations of rat vascularsmooth muscle cells as discriminated by calcium
release mechanisms from internal stores. Circ.Res.
69, 551-556, 1991.
19. Masuo M, Toyo-oka T, Shin WS. and Sugimoto T.
Growth-dependent alterations of intracellular Ca2+handling mechanisms of vascular smooth muscle
cells. Circ.Res. 69, 1327-1339, 1991.
20. Suzuki T, Toyo-oka T, Shin WS, and Sugimoto T.
Cell growth-dependent expression of endothelin-1
provocable Ca2+ channels in cloned vascular smoothmuscle cells. J.Cardiovasc. Pharmacol. 17 (Suppl. 7),
S187-S189, 1991.
21. Toyo-oka T, Aizawa T, Suzuki N, Hirata Y, Miyauchi
T, Shin WS, Yanagisawa M, Masaki T. and Sugimoto
T. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic
angina pectoris. Circulation 83, 476-483, 1991.
22. Toyo-oka T. and Sugimoto T. Endothelin: Key tocoronary vasospasm? Circulation 84, 1451-1452,
1991.
23. Shin WS, Sasaki T, Kato M, Hara K, Seko A, Yang
WD, Shimamoto N, Sugimoto T. and Toyo-oka T.
Autocrine and paracrine effects of endotheliumderived relaxing factor on intracellular Ca 2+ ofendothelial cells and vascular smooth muscle cells:
Identification by two-dimensional image analysis in
coculture. J.Biol.Chem. 267, 20377-20382, 1992.
24. Toyo-oka T, Nagayama K, Suzuki J. and Sugimoto T.
Noninvasive assessment of cardiomyopathy development with simultaneous measurement of topical 1Hand 31P-magnetic resonance spectroscopy. Circulation
86, 295-301, 1992.

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25. Toyo-oka T, Wang YP, Inukai M. and Sakamoto A.
An endothelin family. Recent Progress in Basic andClinical Sciences. Coronary Artery Dis. 2 (Review inDepth), 65-71, 1993.
26. Sakamoto A, Yanagisawa M, Sawamura T, Enoki T,
Ohtani T, Sakurai T, Nakao K, Toyo-oka T. andMasaki T. Distinct subdomains of human endothelin
receptors determine their selectivity to endothelinAselective antagonist and endothelinB-selective agonists. J.Biol.Chem. 268, 8547-8553, 1993.
27. Yang W, Ando J, Korenaga R, Toyo-oka T. andKamiya A. Exogenous nitric oxide inhibits proli-feration of cultured vascular endothelial cells.
Biochem.Biophys.Res.Commun. 203, 1160-1167,
1994.
28. Uehara Y, Hirawa N, Kawabata Y, Suzuki T, Ohshima
N, Oka K, Ikeda T, Goto A, Toyo-oka T, Kizuki K.
Long-term infusion of kallikrein attenuates renal
injury in Dahl salt-sensitive rats. Hypertension 24,
770-778, 1994.
29. Korenaga R, Ando J, Tsuboi H, Yang W, Sakuma I,
Toyo-oka T. and Kamiya A. Laminar flow stimulatesATP- and shear stress-dependent nitric oxide production in cultured bovine endothelial cells.
Biochem.Biophys.Res.Commun. 198, 213-219, 1994.
30. Sakamoto A, Yanagisawa M, Tsujimoto G, Nakao K,
Toyo-oka T. and Masaki T. Pseudo-noncompetitive
antagonism by BQ123 of intracellular calcium transients mediated by human ETA endothelin receptor.
Biochem.Biophys.Res.Commun.200, 679-686, 1994.
31. Kato M, Takazawa K, Kimura A, Ruegg JC, Amano K,
Wang Y, Sakaki Y. and Toyo-oka T. Altered actin
binding with myosin mutation in hypertrophic cardiomyopathy and sudden death. Lancet 345, 1247,
1995.
32. Shin WS, Kawaguchi H, Sasaki T, Wang YP, Yang
WD, Inukai M. and Toyo-oka T.. The role of nitricoxide in cardiovascular system. Ann.N.Y.Acad.Sci.
786, 233-244, 1996.
33. Wang YP, Shin WS, Kawaguchi H, Inukai M, Kato M,
Sakamoto A, Uehara Y, Miyamoto M, Shimamoto N,
Korenaga R, Ando J. and Toyo-oka T. Contribution ofsustained Ca2+ elevation for nitric oxide production inendothelial cells and subsequent modulation of Ca2+transient in vascular smooth muscle cells in coculture. J.Biol.Chem. 271, 5647-5655, 1996.
34. Toyo-oka T. and Naylor WG. Third generation calcium entry blockers. Blood Pressure 5, 206-208, 1996.
35. Kawaguchi H, Shin WS, Wang Y, Inukai M, Kato M,
Matsuo-Okai Y, Sakamoto A, Kaneda Y, and Toyooka T. Apoptosis-like myocardial cell death withoverexpression of human ecNOS gene-Identification
by Sendai virus-coated liposomes and in vivo genetransfection-. Circulation 95, 2441-2447, 1997.
36. Sakamoto A, Ono K, Abe M, Jasmin G, Eki T,
Murakami Y, Masaki T, Toyo-oka T, and Hanaoka, F.
Both hypertrophic and dilated cardiomyopathy arecaused by mutation of the same gene, δ-sarcoglycan,
in hamster. Proc.Natl.Acad.Sci.USA. 94, 1387313878, 1997.

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37. Iwasawa K, Nakajima T, Hazama H, Goto A, Shin
WS, Toyo-oka T and Omata M. Effects of extracellular pH on receptor-mediated Ca2+ influx in A7r5 rat
smooth muscle cells. J.Physiol. 503, 237-251, 1997.
38. Nagoshi H, Uehara Y, Kanai F, Maeda S, Ogura T,
Goto A, Toyo-oka T, Esumi H, Shimizu T and Omata
M. Prostaglandin D2 inhibits inducible nitric oxide
synthase expression in rat vascular smooth muscle.
Circ.Res. 82, 204-209, 1998.
39. Shimamoto R, Suzuki J, Nishikawa J, Fujimori Y,
Nakamura F, Shin WS, Tomaru T and Toyo-oka T.
Measuring the diameter of coronary arteries on MR
angiograms using spatial profile curves. Am.J.Roent.
170, 889-893, 1998.
40. Suzuki J-i, Shimamoto R, Nishikawa J, Fujimori Y,
Nakamura F, Shin WS, Tomaru T and Toyo-oka T.
Vector analysis of the hemodynamics of atherogenesis in the human thoracic aorta with use of MR
velocity mapping. Am.J.Roent. 171, 1285-1290, 1998.
41. Suzuki J-i, Shimamoto R, Nishikawa J, Yamazaki T,
Tsuji T, Nakamura F, Shin WS, Nakajima F, Toyooka T, Ohotomo K. Morphological onset and early
diagnosis in apical hypertrophic cardio- myopathy: along-term analysis with nuclear magnetic resonanceimaging. J.Am.Coll.Cardiol. 33, 146-151, 1999.
42. Kawada T, Shin WS, Nakatsuru Y, Koizumi T,
Sakamoto A, Nakajima T, Nakazawa M, Sato H
Takato T, Ishikawa T and Toyo-oka T. Precise identification of gene-products in hearts after in vivo genetransfection, using Sendai virus-coated proteoliposomes. Biochem.Biophys.Res.Commun. 259, 408413, 1999.
43. Hirawa N, Uehara Y, Kawabata Y, Numabe A, Gomi
T, Ikeda I, Suzuki T, Goto A, Toyo-oka T and Omata
M. Long-term inhibition of renin-angiotensin system
sustains memory function in aged Dahl rats.
Hypertension 34, 496-502, 1999.
44. Kawada T, Nakatsuru Y, Sakamoto A, Koizumi T,
Shin WS, Okai-Matsuo Y, Suzuki J, Uehara Y,
Nakazawa M, Satoh H, Ishikawa T and Toyo-oka T.
Strain- and age-dependent loss of sarcoglycan complex in cardiomyopathic hamster hearts and its reexpression by d-sarcoglycan gene transfer in vivo.
F.E.B.S.Lett. 458, 405-408, 1999.
45. Shin WS, Tanaka M, Suzuki J, and Toyo-ok T. A
novel homoplamic mutation in mtDNA with a single
evolutionary origin as a risk factor for cardiomyopathy. Am.J.Hum.Genet. 67, 1617-1620, 2000.
46. Chen J, Wang YP, Nakajima T, Iwasawa K, Hikiji H,
Sunamoto M, Yoshida Y, Sakaki Y, and Toyo-oka T.
Autocrine action and its underlying mechanism of
nitric oxide on intracellular Ca2+ homeostasis in vascular endothelial cells. J.Biol.Chem. 275,2873928749, 2000.
47. Wang YP, Chen J, Wang Y, Taylor CW, Hirata Y,
Hagiwara H, Mikoshiba K, Toyo-oka T, Omata M,
and Sakaki Y. Crucial role of type 1, but not type 3,
IP3 receptors in IP3-induced Ca2+ release, capacitative
Ca2+ entry and proliferation of A7r5 vascular smoothmuscle cells. Circ.Res. 88, 202-299, 2001.

48. Kawada T, Sakamoto A, Nakazawa M, Urabe M,
Masuda F, Hemmi C, Wang Y, Shin WS, Nakatsuru
Y, Sato H, Ozawa K and Toyo-oka T. Morphologicaland physiological restorations of hereditary form of
dilated cardiomyopathy by somatic gene therapy.
Biochem.Biophys.Res.Commun. 284, 431-435, 2001.
49. Shin WS. Hemmi C and Toyo-oka T. Coculture andcross talk between endothelial cells and vascularsmooth muscle cells mediated by intracellular Ca2+.
Methods in Molecular Biology, Ed. C. Wise, Medical
Research Council Press (London), 347-357, 2001.
50. Kawada T, Nakazawa M, Nakauchi S, Yamazaki K,
Shimamoto R, Urabe M, Nakata J, Hemmi C, Masui
F, Nakajima T, Suzuki J, Monahan J, Sato H, Takeo
S, Ozawa K and Toyo-oka T. Rescue of hereditary
form of dilated cardiomyopathy by rAAV-mediatedsomatic gene therapy.Proc.Natl.Acad.Sci.USA. 99,
901-906, 2002.

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