Olfactomedin 2 Promotes Atherosclerosis by Eliciting Smooth Muscle Foam Cell Formation

Atherosclerosis is a chronic vascular disease with a complex pathophysiology involving smooth muscle cell (SMC) dysfunction, and Olfm2 (olfactomedin 2) plays a role in SMC phenotype modulation. However, it is unclear if Olfm2 is involved in the development of atherosclerosis.

Olfm2 global and SMC-specific knockout models were used to study its role in the development of atherosclerosis.

We found that Olfm2 was upregulated in atherosclerotic plaques of high-fat diet-fed ApoE^-/- (apolipoprotein E) mice in vivo and in oxLDL (oxidized low-density lipoprotein)-treated SMCs in vitro, suggesting the involvement of Olfm2 in SMC foam cell formation (SFCF). Indeed, knockdown of Olfm2 inhibited, while overexpression of Olfm2 promoted oxLDL-induced SFCF. Moreover, lipid accumulation and atherosclerotic lesion areas were significantly reduced in the aortas of high-fat diet-fed Olfm2^-/- ApoE^-/- mice compared with those in ApoE^-/- mice, demonstrating that Olfm2 is a novel regulator promoting atherosclerosis. Mechanistically, Olfm2 physically interacted with IκBα (inhibitor of nuclear factor κB) and facilitated the release of NF-κB (nuclear factor κB) from the NF-κB/IκBα complex, leading to activation of NF-κB signaling, which, in turn, promoted SFCF and subsequent atherosclerosis development. Olfm2 functions in atherosclerosis and SFCF were further confirmed by using an inducible SMC-specific Olfm2-deficient mouse model.

Olfm2 is a novel regulator that promotes SFCF and atherosclerosis by activating NF-κB signaling. Targeting Olfm2 may be a novel potential therapeutic strategy against atherosclerosis.