1992 Fiscal Year Final Research Report Summary
Deletion of mitochondrial DNA in mice induced by the administration of doxorubicin is improved by coenzyme Q10
| Project/Area Number |
03670472
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kurume University |
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Principal Investigator |
ADACHI Kyo Kurume Univ., Sch.of Med., Assoc.Prof., 医学部, 助教授 (30131741)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Toshiaki Kurume Univ., Sch.of Med., Assist., 医学部, 助手 (30224075)
NOZUHARA Akira Kurume Univ., Sch.of Med., Assist., 医学部, 助手 (30198600)
MAYUMI Fumihito Kurume Univ., Sch.of Med., Assist., 医学部, 助手 (60199916)
YAMAMOTO Kiichiro Kurume Univ., Sch.of Med., Assist., 医学部, 助手 (00210526)
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| Project Period (FY) |
1991 – 1992
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| Keywords | idiopathic cardiomyopathy / immunohistochemistry / adriamycin cardiomyopathy / PCR method / mitochondria DNA / coenzyme Q10 / free radical |
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| Research Abstract |
In order to investigate the multiple mitochondrial DNA (mtDNA) deletions in the cardiomyocytes of patients with cardiomyopathy recently discovered, we have experimented with doxorubicin (adriamycin ; ADR) to induce cardiotoxicity in mice. Using a polymerase chain reaction (PCR), the mtDNA was amplified from cardiac specimens in four-week-old Balb/c mice administered ADR at various dosages per week. Mice were sacrificed at Week 4, 8 and 12, and the hearts were resected for mtDNA extraction. Whole circular mtDNA was examined by PCR and a deletion confirmed by primer-shift PCR was detected at ca. 4kb. We identified this mtDNA deletion in 3 (20%) of 15 mice at Week 4, in 7 (58%) of 12 at Week 8, and in 13 (87%) of 15 at Week 12. Consistent results at various ADR dosages confirmed a dosage-independent effect inducing this deletion. No control mice demonstrated this mtDNA deletion. We propose that ADR-induced cardiotoxicity with 4 kb deletion of mtDNA in mouse may be an efficient experimenta
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l model to further investigate the clinical multiple deletions found in cardiomyopathy to determine the pathogenesis of such deletions and whether they are produced primarily or secondarily in clinical cardiomyopath.
Next, we investigate the effectiveness of Coenzyme Q_<10>(CoQ_<10>) in preventing this mtDNA deletion and the effect, if any, of free radical (FR) on the production of the deletion. DOX was administered to mice at dosages of 1mg/kg/week (Grp 1) and 2 mg/kg/week (Grp 2) in the presence or absence of CoQ_<10> (5mg/kg/day and 10mg/kg/day), for 12 weeks. MtDNA isolated from the heart was examined by polymerase chain reaction and the lipid per-oxide content in the mitochondria by malondialdehyde (MDA) formation. The production of the mtDNA 4 kb deletion was decreased by CoQ_<10>, though not quantitatively. In mitochondrial fraction of the myocardium, the MDA was increased by DOX in both Grps, and by the simultaneous administration of CoQ_<10> (5mg/kg/day) the MDA was decreased by 19% in Grp 1, and by 44% in Grp 2 as compared to that of non-CoQ_<10> controls. These studies demonstrate that CoQ_<10> may have a beneficial role of reducing mtDNA deletion in DOX-induced cardiotoxicity, and the MDA results support an FR involvement in this DOX-induced cardiotoxicity. Less
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[Publications] Ozawa T, Tanaka M, Sugiyama S, Hattori K, Ito T, Ohno K, Takahashi A, Sato W, Takada G, Mayumi B, Tamamoto K, Adachi K, Koga Y, Toshima H: "Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy" Biochem Biophys Commun. 170. 830-836 (1990)
Description
「研究成果報告書概要(欧文)」より
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