Reconstituted HDL: A Therapy for Atherosclerosis and Beyond

Andrew J Murphy; Jaye Chin-Dusting; Dmitri Sviridov


Clin Lipidology. 2009;4(6):731-739. 

In This Article

rHDL Particles

Circulating plasma HDL is characterized by its major protein component, apoA-I.[7,8] The interaction of apoA-I with phospholipids (PLs), either ABCA1 mediated or by passive acquisition, gives rise to a species of HDL known as pre-β HDL. This discoidal species of HDL generally contains two apoA-I molecules bound around a PL center, and is the species that rHDL is modeled from. Importantly, the structure and composition of rHDL is open to manipulation and could perhaps be designed for specific purposes, for example, loading the apoA-I molecules with specific PLs that may have stronger anti-inflammatory effects than others.[9]

In addition to varying the PL content, different apoA-I molecules can also be employed to change the function of rHDL molecules. These include the naturally occurring cardioprotective variants apoA-IMilano and apoA-IParis, which have a cysteine-to-arginine substitution at residue 173 and 151, respectively.[10,11] The cysteine is unique to these variants as wild-type apoA-I does not contain any cysteine residues. Homodimers of these variants form disulfide bonds. However, this appears to have no effect on their ability to bind dimyristoylphosphatidylcholine (DMPC) or promote cholesterol efflux.[12–14] Moreover, although both mutations in heterozygous individuals have decreased levels of circulating HDL, these individuals also have a decreased risk of developing atherosclerosis.[10,11,14] Subsequently, an elegant study by Nissen and colleagues demonstrated the effectiveness of apoA-IMilano–PL complex (rHDLMilano) infusions on reducing atheroma volume in patients suffering from coronary atherosclerosis.[15] Another naturally occurring variant of apoA-I that appears to have increased cardioprotective functions contains a valine-to-lysine substitution at residue 156 (V156K).[16] The V156K-rHDL has been demonstrated to have superior antioxidant and anti-inflammatory effects in vivo and to be less susceptible to myeloperoxidase oxidation in comparison with wild-type apoA-I; however, it does not appear to have enhanced functions over apoA-IMilano.[17–19]

In addition to the naturally occurring variants of apoA-I, protein engineering has enabled the development of a trimeric apoA-I complex. By fusing apoA-I to the trimerization domain of human tetranectin, Graversen and colleagues developed a variant of apoA-I that exhibits prolonged plasma retention compared with native apoA-I.[20] Furthermore, this novel trimeric apoA-I complex was shown to be biologically active, promoting cholesterol efflux, interacting with lecithin cholesterol acyltransferase and reducing the progression of atherosclerosis in LDL receptor-deficient (LDLr−/−) mice.[20]


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