Zbp1 promotes atherosclerosis and lesion necrosis in mice.

BACKGROUND AND AIMS: An AKRxDBA/2 mouse strain intercross identified an atherosclerosis modifier gene within a small region on chromosome 2, containing only three protein coding genes, including Z-DNA binding protein 1 (Zbp1), which plays a role in non-canonical necroptosis. We aimed to determine if knockout (KO) of Zpb1 decreased lesion and necrotic areas in mice. METHODS: Zpb1 isoform specific expression was assessed by RNAseq in mouse macrophages and aortic arches. Necroptosis was assessed in cultured mouse macrophages. Hyperlipidemia was induced by weekly injection of an antisense oligonucleotide targeting the mouse LDL receptor gene, combined with feeding a Western-type diet. Lesions were assessed in the aortic root and brachiocephalic artery in both sexes separately and after adjusting for sex in combined analyses. RESULTS: Both AKR and DBA/2 strains express two isoforms of Zbp1 mRNA with higher expression in the DBA/2 atherosclerosis-sensitive strain. Zbp1 KO and wildtype (WT) macrophages were equally susceptible to canonical and non-canonical necroptosis. There were some sex specific effects of the KO in body weight, organ weights, and plasma cholesterol values. In both sexes, KO mice trended towards, or had significantly smaller, lesion areas and necrotic cores, which were significant in combined sex analyses. Lesion cell compositions were qualitatively similar in KO and WT mice. CONCLUSIONS: Zbp1 is an atherosclerosis modifier gene, similar to the canonical necroptosis genes Ripk1 and Mlkl. Higher expression of Zbp1 in DBA/2 mice may play a role in this strain having the largest lesions of all strains tested in the Apoe-deficient background.