Genetic manipulation of the ApoF/Stat2 locus supports an important role for type I interferon signaling in atherosclerosis

Abstract

Apolipoprotein F (ApoF) is a sialoglycoprotein that is a component of the HDL and LDL fractions of human serum. We sought to test the hypothesis that ApoF plays an important role in atherosclerosis in mice by modulating lipoprotein function. Atherosclerosis was assessed in male low density lipoprotein receptor knockout (LDLR KO) and ApoF/LDLR double knockout (DKO) mice fed a Western diet for 16 weeks. ApoF/LDLR DKO mice showed a 39% reduction in lesional area by en face analysis of aortas (p<0.05), despite no significant differences in plasma lipid parameters. ApoF KO mice had reduced expression of Interferon alpha (IFNα) responsive genes in liver and spleen, as well as impaired macrophage activation. Interferon alpha induced gene 27 like 2a (Ifi27l2a), Oligoadenylate synthetases 2 and 3 (Oas2 and Oas3) were significantly reduced in the ApoF KO mice relative to wild type controls. These effects were attributable to hypomorphic expression of Stat2 in the ApoF KO mice, a critical gene in the Type I IFN pathway that is situated just 425 base pairs downstream of ApoF. These studies implicate STAT2 as a potentially important player in atherosclerosis, and support the growing evidence that the Type I IFN pathway may contribute to this complex disease.

Structure-function relationships of HDL in diabetes and coronary heart disease

“…Interestingly, the additional KO of Apof decreased atherosclerosis in Ldlr-KO mice. This effect, however, could not be causally related to the lack of apoF because the Apof KO was associated with hypomorphic expression of the closely linked Stat2 gene (60). The previously reported inverse correlation between plasma levels of apoF and triglycerides (61,62) is in agreement with our finding of low apoF levels in HDL T2DM and HDL T2DM+CHD (Supplemental Figure 3).…”

Interferons as Essential Modulators of Atherosclerosis

“…[45][46][47][48] Overall, the role of IFN-γ in atherosclerosis has been investigated thoroughly, 27,28,32,[49][50][51] whereas research on the role of T1 IFNs in atherosclerosis development has only recently started. 26,52,53 Table 2 summarizes important murine atherosclerotic studies on the T1 and T2 IFNs. In this review, we will further highlight their function in endothelial activation, cell recruitment to the atherosclerotic plaque, foam cell formation, and regulation of apoptosis.…”

Interferon-α adjuvant therapy decreases the recurrence of early clear cell renal cell carcinoma and improves the prognosis of Chinese patients

“…These findings suggest that the STAT pathway might be induced by biological factors in ccRCC. Moreover, IFN signaling was shown to regulate the STAT pathway in 2014 [ 18 ], which further supported evidence that the IFN pathway contributes to complex diseases. Theoretically, the relationship between the IFN pathway and STAT expression may prevent the recurrence of ccRCC.…”