Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis

Abstract

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 of ABCA1 calpain-mediated degradation is a and to HDL and and potential of 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 of ABCA1 calpain-mediated degradation is a and to HDL and and potential of HDL a in the of by to the to and is to be generation of HDL is of the in the of this of of of and of to be in HDL of and by apolipoprotein in and of lipid and in the gene of ABCA1 the of this gene is in in in and is by in the gene of ABCA1 is regulated the and by calpain-mediated ABCA1 is this degradation by by in ABCA1 degradation by and of ABCA1 by and of by and by by increasing degradation of or is in enhanced ABCA1 degradation in a of HDL by by inhibition of proteolytic degradation of ABCA1 is a potential increasing ABCA1 degradation and its inhibition results in increased ABCA1 to the ABCA1 to by inhibiting its degradation and HDL inhibition of of ABCA1 also its in the ABCA1 to by inhibiting its degradation and HDL HDL in both the ABCA1 to by inhibiting its degradation and HDL of ABCA1 degradation or therefore be a potential to HDL biogenesis of is to reduce plasma HDL of by by inhibiting HDL biogenesis inhibition of lipid by and a and plasma in probucol of ABCA1 also inhibits its degradation ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic We in the oxidized of probucol enhanced HDL by inhibiting of the compounds in this of ABCA1 degradation without inhibiting its We therefore the of spiroquinone and the potential of probucol antioxidant activity of probucol in in probucol degradation in to ABCA1 activity and degradation HDL in and in and to the of in a and in in a of and to by the a of in the of by and of by and in in a of and of probucol and its products, and and by the of probucol antioxidant activity of probucol in in probucol degradation and by of of of and the in or to a inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic or a in inhibition of lipid by lipid of and the in the of plasma by a and and of the probucol or by the compounds to by in to a in the of lipid by the HDL of apolipoprotein in or by the and in and of compounds also given a by the in the of the compounds and and the of HDL generation by in a in by the to the in and and the to the of the in the of the in by ABCA1 by and and by a by and by in a in the of and by ABCA1, and of ABCA1 and the of the of ABCA1 by a to ABCA1, the ABCA1 to and of degradation of ABCA1, or to the of ABCA1 and or in and in the and ABCA1 by by ABCA1 in the by of the and its by ABCA1 to by inhibiting its degradation and HDL of ABCA1 by of ABCA1 and of the of ABCA1 in the ABCA1 to by inhibiting its degradation and HDL of ABCA1, and in of and to Expression of by and of of the a in a and a of ABCA1 in the plasma the of the and HDL and by and of by and its by the Expression of ABCA1 in the by and by or and also by of and in by and and lipid deposition in the antiatherogenic of the by the in the and and to the of lipid activity in antioxidant activity of the compounds in or probucol of the of the antioxidant activity by its activity to reduce to by of a of and its and the by and by the of to the in in plasma by by plasma and of and by and of the by by and and to and lipid by of and by probucol inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and enhanced the lipid ABCA1 increased by probucol in of inhibition of HDL ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and also increased of and antioxidant activity of probucol in in probucol degradation to a the and in a ABCA1 increased in the of the in ABCA1 by and also in the of to calpain-mediated ABCA1 degradation ABCA1 to by inhibiting its degradation and HDL in a when and given to or in a the of ABCA1 by to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic of and in the the of of the of compounds and of in the and the of ABCA1 in the of Both and this in a to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibition of ABCA1 by of ABCA1 by by and in the ABCA1 in the increased by in the of ABCA1 degradation by compounds to be by inhibiting of ABCA1 ABCA1 to by inhibiting its degradation and HDL of and of ABCA1 examined by in of by and of of of its and increased the the and also increased the of lipid by of ABCA1 by and degradation of ABCA1 in the of in and by and and and of the results by is and of and to the the ABCA1 by and the and the ABCA1 the ABCA1 by and in of in of by of the a in plasma by the of the in and of and by the the in to and given to to in in plasma and of hepatic ABCA1 in by and in hepatic ABCA1 probucol antioxidant activity and its to be to this antioxidant activity of antioxidant activity probucol products, examined in in to Although antioxidant activity in plasma increased in the in plasma antioxidant activity a of and the results in cholesterol-fed and in and and increased in a and in its the of in the of the and a in in the treatment. increased a the in ABCA1 in the by or the of the in the of and plasma compounds given and ABCA1 and antioxidant activity the given probucol and and given in a to in the in of in of and plasma or given to the in of the and to the in to the of and the vascular in the cholesterol-fed deposition in examined by lipid the and the and and the the the be and the be the and of decreased by the the of in the in lipid deposition both and deposition a of to in and and the of and the lipid deposition be to the of HDL in of of and vascular lipid in cholesterol-fed rabbits. of the in lipid in the by in the and by by the in of the the of the the and the whether inhibition of ABCA1 degradation HDL and plasma HDL to potential degradation of ABCA1, oxidized of the ABCA1 probucol antioxidant activity of probucol in in probucol degradation of probucol increased HDL decreased of and to ABCA1 and HDL Both compounds ABCA1 calpain-mediated degradation without its also increased of in a compounds increased plasma HDL in by increasing hepatic ABCA1 and lipid deposition in the of cholesterol-fed rabbits. conclude compounds HDL ABCA1 degradation and reduce in the of antioxidant to be of the antiatherogenic of probucol in the of in of probucol to its in degradation in and the of in the compounds antioxidant activity in inhibition of ABCA1 degradation could ABCA1 and plasma HDL and in a of in and to of ABCA1 degradation by inhibiting of ABCA1, a calpain-mediated ABCA1 to by inhibiting its degradation and HDL by inhibition of the this the of and be to the of in in of ABCA1 in the ABCA1 degradation by the of ABCA1 to by inhibiting its degradation and HDL both and and the compounds of ABCA1 to its is whether and by or and to a in the results be is probucol ABCA1 HDL inhibiting ABCA1 degradation and the be a in this to the the of results a of the of a or by inhibiting or compounds be potential to HDL and of by inhibiting ABCA1 to be compounds and to be to the be a in the and and be its in antioxidant activity of probucol in in probucol degradation is in of the of in and the inhibiting degradation of and is of gene HDL by inhibiting the activity of ABCA1 inhibition of lipid by and plasma in ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibits lipid of probucol in inhibition of in this probucol to of of and in of probucol in is also to in of its to of the of in of probucol to its in degradation in and the of in the and in the We probucol to HDL inhibiting degradation ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic the a in oxidized of probucol the to ABCA1 degradation HDL by the in of in ABCA1 in to the ABCA1, probucol to in activity of in plasma probucol treatment. to in or of in by a the of the of in by or in or in the of or in the of the and plasma in the of and in in the of and be to increased in the plasma of the by in and this the of plasma HDL by and in this HDL a in the of by to the to and is to be generation of HDL is of the in the of this of of of and of to be in HDL of and by apolipoprotein in and of lipid and in the gene of ABCA1 the of this gene is in in in and is by in the gene Expression of ABCA1 is regulated the and by calpain-mediated ABCA1 is this degradation by by in ABCA1 degradation by and of ABCA1 by and of by and by by increasing degradation of or is in enhanced ABCA1 degradation in a of HDL by by inhibition of proteolytic degradation of ABCA1 is a potential increasing ABCA1 degradation and its inhibition results in increased ABCA1 to the ABCA1 to by inhibiting its degradation and HDL inhibition of of ABCA1 also its in the ABCA1 to by inhibiting its degradation and HDL HDL in both the ABCA1 to by inhibiting its degradation and HDL of ABCA1 degradation or therefore be a potential to HDL biogenesis of is to reduce plasma HDL of by by inhibiting HDL biogenesis inhibition of lipid by and a and plasma in probucol of ABCA1 also inhibits its degradation ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic We in the oxidized of probucol enhanced HDL by inhibiting of the compounds in this of ABCA1 degradation without inhibiting its We therefore the of spiroquinone and the potential of probucol antioxidant activity of probucol in in probucol degradation in to ABCA1 activity and degradation HDL in and in and to the of in a and in in a of and to by the a of in the of by and of by and in in a of and of probucol and its products, and and by the of probucol antioxidant activity of probucol in in probucol degradation and by of of of and the in or to a inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic or a in inhibition of lipid by lipid of and the in the of plasma by a and and of the probucol or by the compounds to by in to a in the of lipid by the HDL of apolipoprotein in or by the and in and of compounds also given a by the in the of the compounds and and the of HDL generation by in a in by the to the in and and the to the of the in the of the in by ABCA1 by and and by a by and by in a in the of and by ABCA1, and of ABCA1 and the of the of ABCA1 by a to ABCA1, the ABCA1 to and of degradation of ABCA1, or to the of ABCA1 and or in and in the and ABCA1 by by ABCA1 in the by of the and its by ABCA1 to by inhibiting its degradation and HDL of ABCA1 by of ABCA1 and of the of ABCA1 in the ABCA1 to by inhibiting its degradation and HDL of ABCA1, and in of and to Expression of by and of of the a in a and a of ABCA1 in the plasma the of the and HDL and by and of by and its by the Expression of ABCA1 in the by and by or and also by of and in by and and lipid deposition in the antiatherogenic of the by the in the and and to the of lipid activity in antioxidant activity of the compounds in or probucol of the of the antioxidant activity by its activity to reduce to by of a of and its and the by and by the of to the in in plasma by by plasma and of and by and of the by by and in in a of and to by the a of in the of by and of by and in in a of and in in a of and to by the a of in the of by and of by and in in a of and of probucol and its products, and and by the of probucol antioxidant activity of probucol in in probucol degradation and by of of of and the in or to a inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic or a in inhibition of lipid by lipid of and the in the of plasma by a and and of the probucol or by the compounds to by in to a in the of products, and and by the of probucol antioxidant activity of probucol in in probucol degradation and by of of of and the in or to a inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic or a in inhibition of lipid by lipid of and the in the of plasma by a and and of the probucol or by the compounds to by in to a in the of lipid by the HDL of apolipoprotein in or by the and in and of compounds also given a by the in the of the compounds and and the of HDL generation by in a in by the HDL of apolipoprotein in or by the and in and of compounds also given a by the in the of the compounds and and the of HDL generation by in a in by the to the in and and the to the of the in the of the in by ABCA1 by and and by a the to the in and and the to the of the in the of the in by ABCA1 by and and by a by and by in a in the of and by ABCA1, and of ABCA1 and the of the of ABCA1 by a to ABCA1, the ABCA1 to and ABCA1 by and by in a in the of and by ABCA1, and of ABCA1 and the of the of ABCA1 by a to ABCA1, the ABCA1 to and of degradation of ABCA1, or to the of ABCA1 and or in and in the and ABCA1 by by ABCA1 in the by of the and its by ABCA1 to by inhibiting its degradation and HDL of ABCA1 by of ABCA1 and of the of ABCA1 in the ABCA1 to by inhibiting its degradation and HDL of ABCA1, and in of and to Expression of by and of of the a in a and a of ABCA1 in the plasma the of the degradation of ABCA1, or to the of ABCA1 and or in and in the and ABCA1 by by ABCA1 in the by of the and its by ABCA1 to by inhibiting its degradation and HDL of ABCA1 by of ABCA1 and of the of ABCA1 in the ABCA1 to by inhibiting its degradation and HDL of ABCA1, and in of and to Expression of by and of of the a in a and a of ABCA1 in the plasma the of the and HDL and by and of by and its by the Expression of ABCA1 in the by and by or and also by of and in by and and lipid deposition in the antiatherogenic of the by the in the and and to the of lipid and HDL and by and of by and its by the Expression of ABCA1 in the by and by or and also by of and in by and and lipid deposition in the antiatherogenic of the by the in the and and to the of lipid activity in antioxidant activity of the compounds in or probucol of the of the antioxidant activity by its activity to reduce to by of a of and its and the by and by the of to the antioxidant activity of the compounds in or probucol of the of the antioxidant activity by its activity to reduce to by of a of and its and the by and by the of to the in in plasma by by plasma and in plasma by by plasma and of and by and of the by by of and by and of the by by and and to and lipid by of and by probucol inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and enhanced the lipid ABCA1 increased by probucol in of inhibition of HDL ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and also increased of and antioxidant activity of probucol in in probucol degradation to a the and in a ABCA1 increased in the of the in ABCA1 by and also in the of to calpain-mediated ABCA1 degradation ABCA1 to by inhibiting its degradation and HDL in a when and given to or in a the of ABCA1 by to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic of and in the the of of the of compounds and of in the and the of ABCA1 in the of Both and this in a to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibition of ABCA1 by of ABCA1 by by and in the ABCA1 in the increased by in the of ABCA1 degradation by compounds to be by inhibiting of ABCA1 ABCA1 to by inhibiting its degradation and HDL of and of ABCA1 examined by in of by and of of of its and increased the the and also increased the of lipid by of in of by of the a in plasma by the of the in and of and by the the in to and given to to in in plasma and of hepatic ABCA1 in by and in hepatic ABCA1 probucol antioxidant activity and its to be to this antioxidant activity of antioxidant activity probucol products, examined in in to Although antioxidant activity in plasma increased in the in plasma antioxidant activity a of and the results in cholesterol-fed and in and and increased in a and in its the of in the of the and a in in the treatment. increased a the in ABCA1 in the by or the of the in the of and plasma compounds given and ABCA1 and antioxidant activity the given probucol and and given in a to in the in of in of and plasma or given to the in of the and to the in to the of and the vascular in the cholesterol-fed deposition in examined by lipid the and the and and the the the be and the be the and of decreased by the the of in the in lipid deposition both and deposition a of to in and and the of and the lipid deposition be to the of HDL in of of and vascular lipid in cholesterol-fed rabbits. of the in lipid in the by in the and by by the in of the the of the the and the and and to and lipid by of and by probucol inhibition of lipid by ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and enhanced the lipid ABCA1 increased by probucol in of inhibition of HDL ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic and also increased of and antioxidant activity of probucol in in probucol degradation to a the and in a ABCA1 increased in the of the in ABCA1 by and also in the of to calpain-mediated ABCA1 degradation ABCA1 to by inhibiting its degradation and HDL in a when and given to or in a the of ABCA1 by to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic of and in the the of of the of compounds and of in the and the of ABCA1 in the of Both and this in a to the probucol ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibition of ABCA1 by of ABCA1 by by and in the ABCA1 in the increased by in the of ABCA1 degradation by compounds to be by inhibiting of ABCA1 ABCA1 to by inhibiting its degradation and HDL of and of ABCA1 examined by in of by and of of of its and increased the the and also increased the of lipid by and given to to in in plasma and of hepatic ABCA1 in by and in hepatic ABCA1 probucol antioxidant activity and its to be to this antioxidant activity of antioxidant activity probucol products, examined in in to Although antioxidant activity in plasma increased in the in plasma antioxidant activity a of and the results in cholesterol-fed and in and and increased in a and in its the of in the of the and a in in the treatment. increased a the in ABCA1 in the by or the of the in the the of and the vascular in the cholesterol-fed deposition in examined by lipid the and the and and the the the be and the be the and of decreased by the the of in the in lipid deposition both and deposition a of to in and and the of and the lipid deposition be to the of HDL in of whether inhibition of ABCA1 degradation HDL and plasma HDL to potential degradation of ABCA1, oxidized of the ABCA1 probucol antioxidant activity of probucol in in probucol degradation of probucol increased HDL decreased of and to ABCA1 and HDL Both compounds ABCA1 calpain-mediated degradation without its also increased of in a compounds increased plasma HDL in by increasing hepatic ABCA1 and lipid deposition in the of cholesterol-fed rabbits. conclude compounds HDL ABCA1 degradation and reduce in the of antioxidant to be of the antiatherogenic of probucol in the of in of probucol to its in degradation in and the of in the compounds antioxidant activity in inhibition of ABCA1 degradation could ABCA1 and plasma HDL and in a of in and to of ABCA1 degradation by inhibiting of ABCA1, a calpain-mediated ABCA1 to by inhibiting its degradation and HDL by inhibition of the this the of and be to the of in in of ABCA1 in the ABCA1 degradation by the of ABCA1 to by inhibiting its degradation and HDL both and and the compounds of ABCA1 to its is whether and by or and to a in the results be is probucol ABCA1 HDL inhibiting ABCA1 degradation and the be a in this to the the of results a of the of a or by inhibiting or compounds be potential to HDL and of by inhibiting ABCA1 to be compounds and to be to the be a in the and and be its in antioxidant activity of probucol in in probucol degradation is in of the of in and the inhibiting degradation of and is of gene HDL by inhibiting the activity of ABCA1 inhibition of lipid by and plasma in ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibits lipid of probucol in inhibition of in this probucol to of of and in of probucol in is also to in of its to of the of in of probucol to its in degradation in and the of in the and in the We probucol to HDL inhibiting degradation ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic the a in oxidized of probucol the to ABCA1 degradation HDL by the in of in ABCA1 in to the ABCA1, probucol to in activity of in plasma probucol treatment. to in or of in by a the of the of in by or in or in the of or in the of the and plasma in the of and in in the of and be to increased in the plasma of the by in and this the of plasma HDL by and in this whether inhibition of ABCA1 degradation HDL and plasma HDL to potential degradation of ABCA1, oxidized of the ABCA1 probucol antioxidant activity of probucol in in probucol degradation of probucol increased HDL decreased of and to ABCA1 and HDL Both compounds ABCA1 calpain-mediated degradation without its also increased of in a compounds increased plasma HDL in by increasing hepatic ABCA1 and lipid deposition in the of cholesterol-fed rabbits. conclude compounds HDL ABCA1 degradation and reduce in the of antioxidant to be of the antiatherogenic of probucol in the of in of probucol to its in degradation in and the of in the compounds antioxidant activity in We inhibition of ABCA1 degradation could ABCA1 and plasma HDL and in a of in and to of ABCA1 degradation by inhibiting of ABCA1, a calpain-mediated ABCA1 to by inhibiting its degradation and HDL by inhibition of the this the of and be to the of in in of ABCA1 in the ABCA1 degradation by the of ABCA1 to by inhibiting its degradation and HDL both and and the compounds of ABCA1 to its is whether and by or and to a in the results be is probucol ABCA1 HDL inhibiting ABCA1 degradation and the be a in this to the the of results a of the of a or by inhibiting or compounds be potential to HDL and of by inhibiting ABCA1 to be compounds and to be to the be a in the and and be its in antioxidant activity of probucol in in probucol degradation is in of the of in and the inhibiting degradation of and is of gene HDL by inhibiting the activity of ABCA1 inhibition of lipid by and plasma in ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic inhibits lipid of probucol in inhibition of in this probucol to of of and in of probucol in is also to in of its to of the of in of probucol to its in degradation in and the of in the and in the We probucol to HDL inhibiting degradation ABCA1 in the plasma to its of apolipoprotein and and to its proteolytic the a in oxidized of probucol the to ABCA1 degradation HDL by the in of in ABCA1 in to the ABCA1, probucol to in activity of in plasma probucol treatment. to in or of in by a the of the of in by or in or in the of or in the of the and plasma in the of and in in the of and be to increased in the plasma of the by in and this the of plasma HDL by and in this a to the of this also to and and to the apolipoprotein spiroquinone