Murine models for study of lipoprotein metabolism and atherosclerosis.

Atherosclerosis is a complex disease that is multifactorial in nature ( 1). While it is clear that alterations in lipoprotein metabolism are etiologically related to atherosclerosis (2), it is equally clear that atherogenesis and its clinical sequalae are determined by many other factors. Even among human subjects homozygous for the same null allele leading to familial hypercholesterolemia, death from cardiovascular causes varies by up to 30 years (3). In an attempt to understand the pathogenesis of this disease, investigators have sought to develop animal models to define the complex events involved and to evaluate therapies designed to ameliorate its consequences. The popularity of individual animal models has waxed and waned over the years. Commonly, rabbits, pigs, pigeons, and subhuman primates have been used, among others. Although rats have been used to study lipoprotein metabolism, only sporadic attempts have been made in the past to use rodents in studies of atherosclerosis. Yet each of these models has been criticized in that they fail to mimic human lipoprotein metabolism or that aortic lesions that develop as a result of a given manipulation were not like that seen in man. While such criticisms may have merit, they nevertheless miss the point that lipoprotein metabolism and atherogenesis are highly complex processes, with many different genetic and environmental events contributing significantly. Dissecting out the individual contributions of all the relevant factors is most difficult, if not impossible, in the human subject. In contrast, a well-thoughtout animal model can yield valuable insights into a defined unit process that can then be integrated into an overall understanding of the complex events involved in atherogenesis. In particular, such criticism of lack of relevancy has been levied upon studies of lipoprotein metabolism and atherosclerosis in mice. However, recent advances in murine genetics, as well as advances in molecular biology and the technology that allows us to transfer genes, as well as inactivate them, have brought into prominence the mouse as an animal model in which to study the unit processes involved. The pioneering work of Paigen and her collaborators has defined atherosclerosis susceptible and resistant strains of mice (4, 5) and mapped candidate genes responsible (6, 7). Rubin et al. (8) have shown that overexpression ofa human apo Al transgene can inhibit fatty streak formation in susceptible mice. Breslow and colleagues (9) and Maeda and colleagues ( 10) have used targeted gene disruption to produce lines of "knockout" mice that lack the gene for apo E. These mice have marked hypercholesterolemia on regular chow as well as on high fat diets, and quickly develop both early as well as late, complex lesions typical ofadvanced atherosclerosis. Granted that the phenotype of these apo E deficient mice differ in many respects from apo E deficient human kindreds, they nevertheless will prove to be of great value in studying individual genetic and environmental influences affecting atherosclerosis susceptibility. In this issue of The Journal, Ishibashi et al. ( 11 ) present a brilliant exposition ofthe power ofmodem techniques to gener-