Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis

Expression of ABCA1 is regulated by transcrip- tion of the gene and calpain-mediated proteolytic degrada- tion, and inhibition ABCA1 degradation results in increased ABCA1 and HDL biogenesis in vitro. We examined whether this approach could be a potential antiatherogenic treat- ment. Although probucol inhibits both the activity and deg- radation of ABCA1, its oxidized products, spiroquinone and diphenoquinone, reduce degradation of ABCA1 with- out inhibiting its activity or altering transcription of the ABCA1 gene. Accordingly, both compounds enhanced apo- lipoprotein A-I/ABCA1-dependent generation of HDL in vitro, and increased hepatic ABCA1 and plasma HDL with- out increasing antioxidant activity in plasma when given to rabbits. Both compounds also decreased vascular lipid de- position in cholesterol-fed rabbits. We therefore conclude that stabilization of ABCA1 against calpain-mediated degra- dation 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. —Arakawa, R., M. Tsujita, N. Iwamoto, C. Ito-Ohsumi, R. Lu, C-A. Wu, K. Shimizu, T. Aotsuka, H. Kanazawa, S. Abe-Dohmae, and S. Yokoyama. Pharmaco- logical inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis. J. Lipid Res . 2009. 50: 2299-2305.