Format

Send to

Choose Destination
See comment in PubMed Commons below
Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):2054-60. doi: 10.1161/ATVBAHA.109.191320. Epub 2009 Oct 8.

Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor.

Author information

1
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, USA. david.masson@laposte.net

Abstract

OBJECTIVE:

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

METHODS AND 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.

PMID:
19815817
PMCID:
PMC2783626
DOI:
10.1161/ATVBAHA.109.191320
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center