Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models

Evidence continues to accumulate from epidemiological studies that elevated plasma concentrations of lipoprotein(a) [Lp(a)] are a risk factor for a variety of atherosclerotic and thrombotic disorders. Lp(a) is a unique lipoprotein particle consisting of a moiety identical to low-density lipoprotein to which the glycoprotein apolipoprotein(a) [apo(a)] that is homologous to plasminogen is covalently attached. These features have suggested that Lp(a) may contribute to both proatherogenic and prothrombotic/antifibrinolytic processes and in vitro studies have identified many such candidate mechanisms. Despite intensive research, however, definition of the molecular mechanisms underlying the epidemiological data has proven elusive. Moreover, an effective and well-tolerated regimen to lower Lp(a) levels has yet to be developed. The use of animal models holds great promise for resolving these questions. Establishment of animal models for Lp(a) has been hampered by the absence of this lipoprotein from common small laboratory animals. Transgenic mice and rabbits expressing human apo(a) have been developed and these have been used to: (i) examine regulation of apo(a) gene expression; (ii) study the mechanism and molecular determinants of Lp(a) assembly from LDL and apo(a); (iii) demonstrate that apo(a)/Lp(a) are indeed proatherogenic and antifibrinolytic; and (iv) identify structural domains in apo(a) that mediate its pathogenic effects. The recent construction of transgenic apo(a) rabbits is a particularly promising development in view of the excellent utility of the rabbit as a model of advanced atherosclerosis.