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High-density lipoprotein metabolism: molecular targets for new therapies for atherosclerosis
M A Kawashiri1, C Maugeais, D J Rader
1University of Pennsylvania Medical Center, 614 BRBII/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
Insights
New therapies targeting high-density lipoprotein (HDL) metabolism are crucial for preventing and treating atherosclerotic cardiovascular disease (ASCVD). Research identifies specific genes for upregulation or inhibition to develop effective treatments.
Area of Science:
- Cardiovascular Medicine
- Lipid Metabolism
- Pharmacogenomics
Background:
- Atherosclerotic cardiovascular disease (ASCVD) necessitates novel therapeutic strategies.
- Plasma high-density lipoprotein (HDL) cholesterol levels correlate inversely with ASCVD risk.
- HDL metabolism pathways offer potential therapeutic targets.
Purpose of the Study:
- To explore gene products involved in HDL metabolism as targets for ASCVD therapies.
- To identify genes suitable for upregulation or inhibition in therapeutic interventions.
Main Methods:
- Review of animal model data to assess the impact of gene products on HDL metabolism.
- Identification of candidate genes for pharmacologic modulation (upregulation or inhibition).
Main Results:
- Genes like apolipoprotein (apo)A-I, apoE, and scavenger receptor B-I (SR-BI) are candidates for upregulation.
- Genes such as apoA-II and cholesteryl ester transfer protein (CETP) are candidates for inhibition.
- The effect of interventions on atherosclerosis may not solely depend on plasma HDL cholesterol levels.
Conclusions:
- Targeting HDL metabolism presents a promising avenue for ASCVD prevention and treatment.
- Pharmacologic manipulation of specific HDL-related genes shows potential for clinical application.
- Clinical trials are anticipated in the next decade to evaluate these novel therapies.
Abstract:
New therapeutic approaches to the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) are needed. Plasma levels of high-density lipoprotein (HDL) cholesterol are inversely associated with risk of ASCVD. Genes involved in the metabolism of HDL represent potential targets for the development of such therapies. Because HDL metabolism is a dynamic process, the effect of a specific HDL-oriented intervention on atherosclerosis cannot necessarily be predicted by its effect on the plasma HDL cholesterol level. Based on available data in animal models, some gene products are candidates for pharmacologic upregulation, infusion, or overexpression, including apolipoprotein (apo)A-I, apoE, apoA-IV, lipoprotein lipase (LPL), ATP-binding cassette protein 1 (ABC1), lecithin cholesterol acyltransferase (LCAT), and scavenger receptor B-I (SR-BI). In contrast, some gene products are potential candidates for inhibition, including apoA-II, cholesteryl ester transfer protein (CETP), and hepatic lipase. The next decade will witness the transition from preclinical studies to clinical trials of a variety of new therapies targeted toward HDL metabolism and atherosclerosis.