Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.
OBJECTIVE
Increasing HDL levels is a potential strategy for the treatment of atherosclerosis.


RESULTS
ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI(-/-) mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr(+/-) mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch -40%, P<0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta.


CONCLUSIONS
Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans.
Masson
David
D
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, USA. david.masson@laposte.net
Koseki
Masahiro
M
Ishibashi
Minako
M
Larson
Christopher J
CJ
Miller
Stephen G
SG
King
Bernard D
BD
Tall
Alan R
AR
D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D004036:Diet, Atherogenic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D010655:Phenylenediamines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D016632:Apolipoprotein A-I; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; C059714:HDL cholesteryl ester; C583499:ITX-5061; D008075:Lipoproteins, HDL; D010655:Phenylenediamines; D047428:Protein Kinase Inhibitors; D011973:Receptors, LDL; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013449:Sulfonamides; D048051:p38 Mitogen-Activated Protein Kinases