Research Articles
Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach

https://doi.org/10.1194/jlr.M057943Get rights and content
Under a Creative Commons license
open access

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate.

high density lipoprotein
apolipoprotein A-I
low density lipoprotein
cholesterol metabolism
cholesteryl ester transport protein
reverse cholesterol transport
in-silico model

Cited by (0)

The online version of this article (available at http://www.jlr.org) contains a supplement.

K. Gadkar and J. Lu contributed equally to this work.

    Abbreviations:

    CE

    cholesteryl ester

    CETP

    cholesteryl ester transport protein

    CI

    confidence interval

    HDL-C

    HDL cholesterol

    IVUS

    intra-vascular ultrasound

    LDL-C

    LDL cholesterol

    LMK

    lipoprotein metabolism and kinetics

    RCT

    reverse cholesterol transport

    rHDL

    reconstituted HDL

    NHP

    nonhuman primate