Adeno-Associated Viruses as a Method to Induce Atherosclerosis in Mice and Hamsters

Atherogenesis involves multiple cell types and organs and can therefore only be recapitulated in animal models. The most widely used mouse models to study atherosclerosis include mice deficient in apolipoprotein E ( Apoe −/− mice) or the low-density lipoprotein receptor ( Ldlr −/− mice).1 Apoe −/− mice develop advanced plaques on a chow diet, which is accelerated by Western-type diet (WTD) feeding, whereas Ldlr −/− mice require WTD feeding to develop advanced atherosclerosis and show only foam cell–rich plaques on chow.1 Wild-type mice do not develop atherosclerotic plaques unless fed with the Paigen diet, but this diet is preferably avoided in these studies because it contains cholate that induces steatohepatitis.1,2Article, see p 1684To study the contribution of genes and pathways to atherogenesis, crossbreeding with the above-mentioned models is required. In this issue of Circulation Research , Bjorklund et al3 propose an alternative to this procedure and elegantly show that a single injection of recombinant adeno-associated virus 8 (rAAV8) expressing either a mouse or a human gain-of-function mutant for proprotein convertase subtilisin/kexin type 9 (PCSK9) in combination with WTD feeding induces atherosclerosis in mice and hamsters. PCSK9 is a secreted protein that is predominantly produced in the liver and binds an extracellular domain of the LDLR to target it to the lysosome for degradation.4 Bjorklund et al3 used rAAV8 expressing mouse D377Y-PCSK9 (rAAV8-D377Y-mPCSK9) or human D374Y-PCSK9 (rAAV8-D374Y-hPCSK9) to induce atherosclerosis in C57BL/6NTac mice.3 For both rAAV8s, stable PCSK9 plasma levels were reached 7 to 14 days after injection, leading to >95% reduced hepatic LDLR abundance. As …