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

Animal Studies

A number of studies in both mouse and rabbit models have now convincingly demonstrated the anti-inflammatory effects of HDL. For example, the introduction of increased levels of apoA-I, by the creation of apoA-I transgenic mice on atherogenic backgrounds (apoE−/− and LDLr−/−) causes a decrease in plaque size and improved vascular tone compared with the relevant controls.[21] Thus, rHDL therapy to increase HDL levels in atherosclerotic susceptible animal models was a natural progression.

The antiatherosclerotic properties of rHDLMilano were confirmed by treating mice with 18 injections (40 mg/kg/injection) of rHDLMilano over 5 weeks. rHDLMilano significantly reduced aortic atherosclerosis, lipid content and macrophage infiltration as well as promoting cholesterol efflux significantly above basal levels.[22] Unfortunately, the lack of a native rHDL arm in the study limited comparisons between rHDL and rHDLMilano. However, studies comparing rHDL and rHDLMilano revealed that the apoA-I variants inhibit atherosclerosis to a similar extent and no increase in function was observed with apoA-IMilano.[23–27] A second group of mice receiving a single dose of 80 mg/kg showed a further reduction in plaque development. This result was encouraging as it suggested that a single dose of rHDLMilano could remodel atherosclerotic plaques. This latter finding prompted a further study to examine the effect of a single bolus infusion of a high dose (400 mg/kg) of rHDLMilano on plaque composition. At 48 h postinfusion, lipid content in plaques was significantly reduced along with a significant reduction in macrophage staining.[28] Interestingly, data from these animal studies suggest that a high-concentration, single-bolus infusion of rHDL may be able to stabilize atherosclerotic plaques. Further studies with a single infusion and a later end point would also be of great interest to determine how long the beneficial effects of HDL last. However, while the results are striking, the practicality of such a high dose translating to human interventions remains a challenge as repeated doses of 80 mg/kg in the Effect of rHDL on Atherosclerosis Safety and Efficacy (ERASE) trial were discontinued owing to abnormal liver function tests.[29]

ApoA-IMilano has also been proven to have beneficial effects in Sprague Dawley rats where it was shown to reduce total and HDL cholesterol and platelet aggregation.[30] In addition, chemically induced thrombosis was delayed and thrombus weight was significantly less compared with control rats. These findings provide the basis for the therapeutic application of either apoA-I or apoA-IMilano in the regression or stabilization of atherosclerotic plaques.

Anti-inflammatory properties of rHDL have also been demonstrated in a rabbit model of vascular inflammation.[9] Nicholls et al. used a non-occlusive periarterial collar to induce infiltration of leukocytes into the arterial wall, an early event in the development of the atherosclerotic plaque. Infusion of rHDL or apoA-I inhibited neutrophil infiltration as well as the expression of VCAM-1 and ICAM-1. In addition, PL vesicles also had an effect on reducing inflammation, possibly through remodeling endogenous HDL and freeing apoA-I molecules.

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