Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation
Atherosclerosis is thought to be initiated by the sub-intimal retention of apolipoprotein-B containing lipoproteins within susceptible sites of the vasculature. Understanding this initiation is not possible with current legacy mouse models of atherosclerosis. We created two mouse strains of inducible hypercholesterolemia based on conditional loss of apolipoprotein E or through inducible expression of a gain-of-function proprotein convertase subtilisin/kexin type 9 D374Y mutation. Both strains rapidly broke plasma-lipid homeostasis and converted to a state of atherogenic dyslipidemia, resulting in overt aortic-accumulation of lipoproteins within 10 days. RNA-sequencing revealed that the vascular response is completely dependent on the route taken to dyslipidemia, which nevertheless implicates known pathogenic pathways in the aetiology of atherosclerosis, and further implicates APOE as an inhibitor of inflammation. As atherosclerosis develops, a convergence of common mechanistic processes emerge in both strains with significant involvement of the immune system, and targeting of CD8 T cells can regulate a conserved aortic response. Our results define atherosclerosis initiation as highly heterogeneous process and identify multiple potential therapeutic targets that may influence disease onset.