Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis[S]
AUTOR(ES)
Arakawa, Reijiro
FONTE
The American Society for Biochemistry and Molecular Biology
RESUMO
Expression of ABCA1 is regulated by transcription of the gene and calpain-mediated proteolytic degradation, and inhibition ABCA1 degradation results in increased ABCA1 and HDL biogenesis in vitro. We examined whether this approach could be a potential antiatherogenic treatment. Although probucol inhibits both the activity and degradation of ABCA1, its oxidized products, spiroquinone and diphenoquinone, reduce degradation of ABCA1 without inhibiting its activity or altering transcription of the ABCA1 gene. Accordingly, both compounds enhanced apolipoprotein A-I/ABCA1-dependent generation of HDL in vitro, and increased hepatic ABCA1 and plasma HDL without increasing antioxidant activity in plasma when given to rabbits. Both compounds also decreased vascular lipid deposition in cholesterol-fed rabbits. We therefore conclude that stabilization of ABCA1 against calpain-mediated degradation is a novel and potentially important strategy to increase HDL formation and prevent atherosclerosis. Spiroquinone and diphenoquinone are potential seeds for development of such drugs.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2759836Documentos Relacionados
- A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I
- Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels
- Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes
- Do DNA sequence variants in ABCA1 contribute to HDL cholesterol levels in the general population?
- Increased ABCA1 activity protects against atherosclerosis