2005 Fiscal Year Final Research Report Summary
Elucidation of the mechanisms for intracellular accumulation of cholesterol ester and its application to therapies.
| Project/Area Number |
16590895
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Showa University |
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Principal Investigator |
MIYAZAKI Akira Showa University, School of Medicine, Professor, 医学部, 教授 (70253721)
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| Co-Investigator(Kenkyū-buntansha) |
HONGO Shigeki Showa University, School of Medicine, Associate Professor, 医学部, 講師 (40054043)
TAKEYA Motohiro Kumamoto University, School of Medicine, Professor, 大学院・医学薬学研究部, 教授 (90155052)
WATANABE Takuya Showa University, School of Medicine, Associate Professor, 医学部, 助教授 (30297014)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Atherosclerosis / macrophage / serotonin / ACAT / foam cell |
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| Research Abstract |
Acyl-coenzyme A : cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. Serotonin (5-HT), a potent vasoconstrictor that is released from activated platelets, increases uptake of oxidized low-density lipoprotein (LDL) by macrophages, leading to foam cell formation, and contributes to the development of atherosclerotic plaque. However, it is not yet known whether 5-HT affects ACAT-1 expression in human monocyte-macrophages as the molecular mechanism of 5-HT-induced foam cell formation. We examined the effects of 5-HT on ACAT-1 expression during differentiation of cultured human monocytes into macrophages. Expression of ACAT-1 protein but not 5-HT_<2A> receptor increased in a time-dependent manner. 5-HT increased ACAT activity in a concentration-dependent manner after seven days in primary monocyte culture. Immunoblotting analysis showed that 5-HT at 10μM increased ACAT-1 protein expression level by two-fold, and this effect was abolished completely by a 5-HT_<2A> receptor antagonist (sarpogrelate), Northern blotting analysis indicated that among the four ACAT-1 mRNA transcripts (2.8-,3.6-,4.3-,and 7.0-kb), the levels of the 2.8- and 3.6-kb transcripts were selectively up-regulated by 〜1.7-fold by 5-HT (10μM). The results of the present study suggested that 5-HT may play a crucial role in macrophage-derived foam cell formation by up-regulating ACAT-1 expression via the 5-HT_<2A> receptor, contributing to the progression of atherosclerotic plaque in the coronary and pulmonary arteries.
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