2005 Fiscal Year Final Research Report Summary
Molecular mechanism of cardiac hypertrophy caused by lipid toxicity
| Project/Area Number |
16590250
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
HORIUCHI Masahisa Kagoshima University, Graduate School of Medical and Dental Sciences, Assistant Professor, 大学院・医歯学総合研究科, 講師 (50264403)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SAHEKI Takeyori Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (10056070)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Keywords | carnitine / cardiac hypertrophy / fatty aicd / JVS mice / pyruvate dehydrogenase kinae / orexin |
|---|
| Research Abstract |
[Purpose] To elucidate the mechanism of the cardiac hypertrophy of JVS mice.
1)We examined the development of cardiac hypertrophy in juvenile visceral steatosis (JVS) mice, a model of systemic carnitine deficiency, by varying the amount of lipid in the diet. Cardiac hypertrophy was markedly attenuated by decreasing soy bean oil (SBO) from 5% (w/w) to 1%. Triglyceride contents of ventricle in JVS mice fed 1% SBO were significantly lower than that in JVS mice fed 5% SBO. Addition of medium-chain triglyceride metabolically utilized by JVS mice did not affect the development of cardiac hypertrophy. On the other hand, the mRNA levels of atrial natriuretic peptide and skeletal α-actin, which are related to cardiac hypertrophy, were also attenuated by decreasing lipid in the diet. Adenylate energy charge and creatine phosphate in the heart of JVS mice at the early stage of hypertrophy were not significantly different from control mice given the same laboratory chow (4.6% of lipid). Although ur
… More
inary prostaglandin F_<2α> was found to be increased in JVS mice at 15 days of age when they developed cardiac hypertrophy, administration of aspirin was not efficacious. We therefore propose that the proportion of lipid in the diet is important in the development of cardiac hypertrophy in carnitine-deficient JVS mice, and that this is not related to prostaglandin formation.
2)We found reduced locomotor activity (LA) under fasting in JVS mice. LA recovered under carnitine or sucrose administration, but not under medium-chain triglyceride. In addition, fasted JVS mice, without any energy supply, were activated by modafinil, a stimulator of the dopamine pathway. These results suggest that the reduced LA is not adequately explained by energy deficit. We found lower percentage of c-Fos positive orexin neurons in the lateral hypothalamus and reduced orexin-A concentration in the cerebrospinal fluid of fasted JVS mice. These results strongly suggest that the reduced LA in fasted jvs^<-/-> mice is related to the inhibition of orexin neuronal activity. Less
|
