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Novel HDL-directed pharmacotherapeutic strategies.

ABSTRACT: The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase.

SUBMITTER: Degoma EM

PROVIDER: S-EPMC3315102 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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Novel HDL-directed pharmacotherapeutic strategies.

Degoma Emil M EM Rader Daniel J DJ

Nature reviews. Cardiology 20110118 5

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabol ...[more]

PMID: 21243009

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Project description:The non-medical use of prescription drugs, in general, and opioids, in particular, is a national epidemic, resulting in enormous addiction rates, healthcare expenditures, and overdose deaths. Prescription opioids are overly prescribed, illegally trafficked, and frequently abused, all of which have created a new opioid addiction pathway, adding to the number of opioid-dependent newborns requiring treatment for neonatal abstinence syndrome (NAS), and contributing to challenges in effective care in maternal and fetal/neonatal (M-F/N) medicine. The standard of care for illicit or prescription opioid dependence during pregnancy is opioid agonist (methadone or buprenorphine) substitution therapy, which are also frequently abused. The next generation of pharmacotherapies for the treatment of illicit or prescription opioid addiction in the M-F/N interactional dyad must take into consideration the interplay between genetic, epigenetic, and environmental factors. Addiction to illicit drugs during pregnancy presents unique challenges to effectively treat the mother, and the developing fetus and infant after delivery. New pharmacotherapies should be safe to the developing fetus, effective in treating the physical and psychological consequences of addiction in the mother, and reduce the incidence and severity of NAS in the infant after birth. More pharmacotherapeutic options should be available to the physician such that a more individualized rather than a one-drug/strategy-fits-all approach can be used. A myriad of new and exciting pharmacotherapeutic strategies for the treatment of opioid dependence and addiction are on the horizon. This review focuses on such three strategies: (i) pharmacotherapeutic targeting of the serotonergic system; (ii) mixed opioid immunotherapeutics (vaccines); (iii) pharmacogenomics as a therapeutic strategy to insure personalized care. We review and discuss how these strategies may offer additional treatment modalities for the treatment of M-F/N during pregnancy and the treatment of the infant after birth.

Project description:Background/objectivesDecreased plasma concentration of high-density lipoprotein cholesterol (HDL-C) is a risk factor linked to increased risk of cardiovascular disease (CVD). Decreased anti-atherogenic properties of HDL are also implicated in increased CVD risk. The cause is unknown but has been linked to impaired glucose tolerance. The aim of this study was to quantify the modification of HDL by methylglyoxal and related dicarbonyls in healthy people and patients with type 2 diabetes characterise structural, functional and physiological consequences of the modification and predict the importance in high CVD risk groups.Subjects/methodsMajor fractions of HDL, HDL2 and HDL3 were isolated from healthy human subjects and patients with type 2 diabetes and fractions modified by methylglyoxal and related dicarbonyl metabolites quantified. HDL2 and HDL3 were glycated by methylglyoxal to minimum extent in vitro and molecular, functional and physiological characteristics were determined. A one-compartment model of HDL plasma clearance was produced including formation and clearance of dicarbonyl-modified HDL.ResultsHDL modified by methylglyoxal and related dicarbonyl metabolites accounted for 2.6% HDL and increased to 4.5% in patients with type 2 diabetes mellitus (T2DM). HDL2 and HDL3 were modified by methylglyoxal to similar extents in vitro. Methylglyoxal modification induced re-structuring of the HDL particles, decreasing stability and plasma half-life in vivo. It occurred at sites of apolipoprotein A-1 in HDL linked to membrane fusion, intramolecular bonding and ligand binding. Kinetic modelling of methylglyoxal modification of HDL predicted a negative correlation of plasma HDL-C with methylglyoxal-modified HDL. This was validated clinically. It also predicted that dicarbonyl modification produces 2-6% decrease in total plasma HDL and 5-13% decrease in functional HDL clinically.ConclusionsThese results suggest that methylglyoxal modification of HDL accelerates its degradation and impairs its functionality in vivo, likely contributing to increased risk of CVD-particularly in high CVD risk groups.

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Novel HDL-directed pharmacotherapeutic strategies.

Publications

Novel HDL-directed pharmacotherapeutic strategies.

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