itx-5061 and Atherosclerosis

Increasing HDL levels is a potential strategy for the treatment of atherosclerosis.. 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.. 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.

Topics: Aged; Animals; Apolipoprotein A-I; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Diet, Atherogenic; Double-Blind Method; Female; Humans; Lipoproteins, HDL; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Transgenic; Middle Aged; p38 Mitogen-Activated Protein Kinases; Phenylenediamines; Protein Kinase Inhibitors; Receptors, LDL; Scavenger Receptors, Class B; Sulfonamides