Reconstituted HDL: A Therapy for Atherosclerosis and Beyond

Andrew J Murphy; Jaye Chin-Dusting; Dmitri Sviridov

Disclosures

Clin Lipidology. 2009;4(6):731-739. 

In This Article

rHDL-based Therapies: New Indications

Arthritis

While HDL therapy is largely aimed at cardiovascular-related diseases, other uses for HDL therapy are being investigated. As previously suggested, a clear property of HDL is that it is anti-inflammatory. The HDL particle has been demonstrated to switch to a proinflammatory molecule in patients with rheumatoid arthritis.[45] Administration of atrovastatin appeared to improve the anti-inflammatory function of the HDL particle, which was accompanied by a trend in reduced hsCRP levels; however, no improvement in clinical condition was observed.[46] Using the collagen-induced arthritis animal model as a model of rheumatoid arthritis, it was demonstrated that administration of the D-4F mimetic peptide along with pravastatin improved the HDL anti-inflammatory index.[47] The improvement in HDL function was correlated with a positive clinical outcome. Furthermore, serum inflammatory molecules were attenuated by the treatment – a finding that also extended to T cell/monocyte cocultures where D-4F plus pravastatin significantly reduced the contact-mediated activation of T cells and subsequent release of a number of cytokines.[47] While D-4F is a mimetic peptide and not a rHDL particle, it is tempting to extrapolate the finding and postulate that rHDL therapy may also be beneficial. Similarly, results obtained from rHDL studies may transition to apoA-I mimetic peptides, as reviewed by Remaley et al.[6,48]

Memory Loss

Lipoprotein metabolism in the brain is dynamic, neurons require a rapid lipid turnover and, thus, RCT is active in the brain too.[49] Low levels of HDL and apoA-I have been correlated with short-term memory loss and Alzheimer's disease (AD).[50,51] Moreover, a polymorphism in the apoA-I gene influences the risk of early-onset nonfamiliar AD.[52] Middle-aged participants of the Whitehall II study were tested for short-term verbal memory with a 5-year follow-up. It was shown that a decrease in short-term verbal memory was associated with a reduction in plasma HDL.[53] While HDL itself cannot cross the blood–brain barrier, apoA-I is not produced in the CNS and it has been demonstrated that apoA-I crosses the blood–brain barrier into the CNS from plasma HDL, forming HDL particles that are also rich in apoE.[54] There are a number of potential mechanisms through which HDL could act to protect neural function. HDL is critical for the maturation of synapses and the maintenance of synaptic plasticity.[50] HDL can suppress the production of amyloid-β (Aβ),[55] and bind excess Aβ, which can form neutrotoxic aggregates that impair memory.[56,57] As HDL is a potent anti-inflammatory molecule, it is also conceivable that HDL could reduce astrocyte inflammation. However, increasing HDL levels or its receptors has yet to be proven to protect from memory loss or to have a direct effect on AD. Furthermore, as only apoA-I appears to be able to cross the blood–brain barrier, the mode of delivery would be challenging.

Drug Delivery

In addition to its antiatherosclerotic effects, HDL can be employed as a targeted drug-delivery vector. An rHDL particle carrying nosiheptide, an anti-hepatitis B virus molecule, has been shown to deliver most of the anti-hepatitis B virus molecule to the liver within 30 min of intravenous infusion in rats.[58] HDL has also been examined as a carrier of anticancer drugs.[59,60] Loading HDL with the anticancer drug paclitaxel and administering the particle to mice revealed that it was tolerated better than the free drug.[59] However, further studies are required to determine if loading HDL with drugs is viable.

Diagnostic & Therapeutic

HDL has also been used as a carrier for MRI contrast agents such as gadolinium for vascular imaging. Atherosclerotic-specific rHDL particles were made using an apoE-derived peptide P2fA2 and loaded with gadolinium.[61] The HDL P2fA2 particle was demonstrated be taken up by macrophages in vitro. Further infusion of the rHDL P2fA2 in apoE−/− mice led to the specific accumulation of the particle in macrophages located in atherosclerotic plaques as no signal was observed in healthy areas of the aorta.[61] This may be a valuable tool for imaging vulnerable plaques in vivo as macrophage infiltration is positively correlated with plaque severity. It would be interesting to determine if these rHDL particles still have antiatherosclerotic effects, which may make the use of these particles more attractive if they can be used for multiple purposes.

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