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

Area of Science:

• Biochemistry
• Pharmacology
• Cardiovascular Medicine

Background:

• Cholesteryl ester transport protein inhibitor drugs failed to decrease cardiovascular disease (CVD) risk despite raising high-density lipoprotein cholesterol (HDL-C).
• This suggests that elevated HDL-C levels do not always correlate with increased reverse cholesterol transport (RCT), the proposed mechanism for HDL's cardioprotective effects.
• Current challenges in drug development include the lack of validated markers to connect drug-induced changes in HDL properties to RCT and subsequent CVD risk reduction.

Purpose of the Study:

• To utilize a systems pharmacology model to analyze the impact of different high-density lipoprotein (HDL) targets on cholesterol metabolism.
• To establish quantitative relationships between HDL-related measurements and alterations in RCT rate.
• To support the selection and evaluation of drug targets and compounds for CVD treatment.

Main Methods:

• Development and application of a systems pharmacology model.
• Simulation of cholesterol metabolism and reverse cholesterol transport under various HDL-modulating scenarios.
• Quantitative analysis of the relationship between HDL parameters and RCT rate.

Main Results:

• Simulations indicate that short-term infusion of HDL may offer potential for treating acute CVD by quantifying peripheral cholesterol removal.
• The study suggests that for primary CVD prevention, stimulating apolipoprotein A-I (ApoA-I) synthesis may be a more effective strategy.
• This approach is favored due to its potential for a sustained long-term increase in RCT rate.

Conclusions:

• Pharmacologic modulation of HDL-C requires careful consideration of effects on RCT, not just HDL-C levels.
• Systems pharmacology modeling provides a valuable tool for evaluating HDL-targeted therapies and their impact on CVD.
• Inducing ApoA-I synthesis shows promise for long-term CVD prevention through enhanced RCT.