1997 Fiscal Year Final Research Report Summary
PATHOPHYSIOLOGICAL ROLE OF SCP2 IN ATHEROSCLEROSIS
| Project/Area Number |
08671135
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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 |
内分泌・代謝学
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| Research Institution | Chiba University |
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Principal Investigator |
HIRAI Aizan CHIBA UNIVERSITY MEDICAL SCHOOL HOSPITAL LECTURER, 医学部, 講師 (10189813)
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| Project Period (FY) |
1996 – 1997
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| Keywords | SCP2 / Lipid transfer protein / ATHEROSCLEROSIS / isoprenoid / Rho A / geranylgeranyl-pyrophosphate / OAM CELL FORMATION / Mevalonate metabolites |
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| Research Abstract |
Sterol carrier protein 2 (SCP_2) has been shown to be involved in intracellular transport and metabolism of cholesterol. However, there have been no reports concerning SCP_2 in macrophages, the major source of atheromatous foam cells. The increment of cellular free cholesterol is responsible for enhanced SCP_2 gene expression in macrophages. The enhancement of SCP_2 gene expression by AcLDL suggests that SCP_2 may play an important role during foam cell formation induced by AcLDL which may be most important step for the atherosclerosis. Cyclin-dependent kinase (Cdk) enzymes are activated for entry into the S phase of the cell cycle. Elimination of Cdk inhibitor protein p27Kipl during the G1 to S phase is required for the activation process. An inhibitor of HMG-CoA reductase prevents its elimination and leads to G1 arrest. Mevalonate and its metabolite, geranylgeranyl-pyrophosphate, but not farnesyl-pyrophosphate, restore the inhibitory effect of pravastatin on the degradation of p27 and allow Cdk2 activation. By the addition of geranylgeranyl-pyrophosphate, Rho small GTPase (s) are geranylgeranylated and translocated to membranes during G1/S progression. The restoring effect of geranylgeranyl-pyrophosphate is abolished with botulinum C3 exoenzyme which specifically inactivates Rho. These results indicate i) among mevalonate metabolites, geranylgeranyl-pyrophosphate is absolutely required for the elimination of p27 followed by Cdk2 activation ; ii) geranylgeranylated Rho small GTPase (s) promote the degradation of p27 during G1/S transition in FRTL-5 cells.
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