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. ### Competing Interest Statement The authors have declared no competing interest. * apoB : Apolipoprotein B APOE : Apolipoprotein E APOE cKO : Conditional knockout of APOE CoA : Coenzyme A D374Y : Conditional knock-in of hPCSK9 D374Y DAPI : 4′,6-diamidino-2-phenylindole DC : Dendritic cell ELISA : Enzyme-linked immunosorbent assay FDR : False discovery rate FH : Familial hypercholesterolemia GC : Germinal center HFD : High fat diet hPCSK9 D374Y : human gain-of-function variant of PCSK9 IgG : Immunoglobulin G IgM : Immunoglobulin M LDL : Low-density lipoprotein LDLR : Low-density lipoprotein receptor MDA-LDL : Malondialdehyde modified LDL MHCII : Major histocompatibility complex II mRNAseq : messenger RNA sequencing PCSK9 : Proprotein convertase subtilisin/kexin type 9 PDGFB : Platelet-derived growth factor subunit B RPM : Mapped reads TGFB : Transforming growth factor beta TPM : Transcripts per million reads mapped VCAM-1 : Vascular cell adhesion molecule-1 VEGF : Vascular endothelial growth factor VLDL : Very low-density lipoprotein