能量代谢紊乱所致心肌肥厚中不同种类1,2 - 二酰甘油的变化

Changes in distinct species of 1,2-diacylglycerol in cardiac hypertrophy due to energy metabolic disorder.

作者信息

Saburi Yoshihiro, Okumura Kenji, Matsui Hideo, Hayashi Kazunori, Kamiya Hiroki, Takahashi Ryotaro, Matsubara Kenichiro, Ito Masafumi

机构信息

Department of Internal Medicine II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

出版信息

Cardiovasc Res. 2003 Jan;57(1):92-100. doi: 10.1016/s0008-6363(02)00608-9.

DOI:10.1016/s0008-6363(02)00608-9

PMID:12504818

Abstract

OBJECTIVE

The juvenile visceral steatosis (JVS) mouse, a genetic model of systemic carnitine deficiency resulting from carnitine transport mutation, develops cardiac hypertrophy. We determined two putative lipid messengers, 1,2-diacylglycerol (DAG) and ceramide, in JVS and carnitine palmitoyltransferase-I (CPT-I) inhibitor etomoxir-treated mice because these lipids function as co-messengers in the myocardium via modification of protein kinase C activity.

METHODS

JVS mice were evaluated at 4 and 8 weeks of age. The effect of long-term etomoxir treatment (45 mg/day) (ET) on mice was investigated in control mice from 4 to 8 weeks of age. As a model of inhibited cardiac hypertrophy, carnitine-treated JVS (CT) mice were produced. Myocardial DAG and ceramide levels and their fatty acid composition were measured.

RESULTS

The heart/body weight ratio increased by 100% in JVS mice compared with that in controls, while that of CT mice was normalized in comparison with controls at 8 weeks of age. DAG markedly increased in both JVS and ET mice compared with that in controls (1,677+/-84, 1,258+/-49, and 585+/-58 ng/dry wt, respectively; P<0.01 for controls versus JVS or ET mice), whereas it was decreased significantly in CT mice compared with that in JVS mice (1,066+/-54 ng/dry wt, P<0.01). Furthermore, the fatty acid composition of DAG was similar in JVS and ET mice; in particular, 18:1 and 18:2 were significantly elevated in the myocardium (P<0.01 versus controls). On the other hand, that of DAG in CT mice was similar to that of the control group. In contrast, no difference was observed in myocardial ceramide levels among the groups.

CONCLUSIONS

Pharmacological intervention with etomoxir mimics changes in the lipid second messenger characteristic of genetic JVS mice. The results suggest that the increases in distinct DAG species might be involved in the pathogenesis of cardiac hypertrophy as a result of disorder of fatty acid transport.

摘要

目的

幼年内脏脂肪变性（JVS）小鼠是一种因肉碱转运突变导致全身性肉碱缺乏的遗传模型，会出现心脏肥大。我们测定了JVS小鼠以及用肉碱棕榈酰转移酶-I（CPT-I）抑制剂依托莫西治疗的小鼠体内两种假定的脂质信使，即1,2 -二酰甘油（DAG）和神经酰胺，因为这些脂质通过修饰蛋白激酶C活性在心肌中作为协同信使发挥作用。

方法

对4周龄和8周龄的JVS小鼠进行评估。研究了4至8周龄的对照小鼠长期接受依托莫西治疗（45毫克/天）（ET）的效果。制备了肉碱治疗的JVS（CT）小鼠作为抑制心脏肥大的模型。测量心肌DAG和神经酰胺水平及其脂肪酸组成。

结果

与对照组相比，JVS小鼠的心脏/体重比增加了100%，而CT小鼠在8周龄时与对照组相比恢复正常。与对照组相比，JVS小鼠和ET小鼠的DAG均显著增加（分别为1,677±84、1,258±49和585±58纳克/干重；对照组与JVS或ET小鼠相比，P<0.01），而与JVS小鼠相比，CT小鼠的DAG显著降低（1,066±54纳克/干重，P<0.01）。此外，JVS小鼠和ET小鼠中DAG的脂肪酸组成相似；特别是，心肌中18:1和18:2显著升高（与对照组相比，P<0.01）。另一方面，CT小鼠中DAG的脂肪酸组成与对照组相似。相比之下，各组之间心肌神经酰胺水平未观察到差异。