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

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

  • Arterioscler Thromb Vasc Biol. 2009 Dec;29(12):2054-60. doi: 10.1161/ATVBAHA.109.191320.
David Masson 1 Masahiro Koseki Minako Ishibashi Christopher J Larson Stephen G Miller Bernard D King Alan R Tall
Affiliations

Affiliation

  • 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.

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