Project/Area Number |
12470032
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Pathological medical chemistry
|
Research Institution | Tohoku University |
Principal Investigator |
TAKASAWA Shin (2001-2002) Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (50187944)
加藤 一郎 (2000) 東北大学, 大学院・医学系研究科, 助手 (50250741)
|
Co-Investigator(Kenkyū-buntansha) |
KAGAYA Yutaka Tohoku University, University Hospital, Lecture, 医学部附属病院, 講師 (90250779)
NATA Koji Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (90202233)
高沢 伸 東北大学, 大学院・医学系研究科, 助教授 (50187944)
|
Project Period (FY) |
2000 – 2002
|
Project Status |
Completed (Fiscal Year 2002)
|
Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2000: ¥5,300,000 (Direct Cost: ¥5,300,000)
|
Keywords | CD38 / cyclic ADP-ribose / knockout mouse / muscle force / intracellular Ca^<2+> / cardiomyocytes / cardiac hypertrophy / カルシウムイオン / 細胞内Ca^<2+>ブール / 心臓肥大 |
Research Abstract |
CD38 catalyzes both the formation and hydrolysis of cyclic ADP-ribose (cADPR). To elucidate whether the CD38/cADPR signaling system plays a significant role in Ca^<2+> cycling in vivo, we analyzed the myocardium of CD38 knockout mice (CD38KO). In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT), and cardiac hypertrophy developed only in males but not in females. At physiological temperature (36.1±0.2℃), none of the parameters for Ca^<2+> transients and forces of papillary muscles differed between WT and CD38KO. In contrast, at lower temperature (26.8±0.2℃), at which the effects of cADPR are supposed to be lost, the peak [Ca^<2+>]I was significantly increased and the time constant of decline in [Ca^<2+>]I and minimum of the first derivative of force were significantly decreased in both-gender CD38KO compared with gender-matched WT. Additionally, in female CD38KO, the maximum of the first derivative of force was significantly increased. Western blot analysis revealed that, in both-gender CD38KO, the expression levels of sarcoplasmic reticulum Ca^<2+> ATPase type 2 (SERCA2) and the SERCA2-to-phospholamban ratio were significantly increased compared with WT. The ryanodine receptor protein level was significantly increased in female CD38KO, but not in male CD38KO, compared with gender-matched WT. These data suggest the CD38/cADPR signaling system plays an important role in intracellular Ca2+ homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender, which might be responsible at least partially for the different hypertrophic responses between genders.
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