Fortilin deficiency induces anti-atherosclerotic phenotypes in macrophages and protects hypercholesterolemic mice against atherosclerosis

In the atherosclerotic intima, macrophages (MΦ) perpetuate chronic inflammation and cholesterol accumulation. Fortilin, a 172-amino-acid multifunctional protein, is abundant in the atherosclerotic intima and promotes atherogenesis, but its mechanism has remained unclear. Herein, we report that fortilin in MФ (fortilin^MΦ) facilitates atherosclerosis by (a) enhancing MΦ survival, proliferation, and lipid uptake, leading to the accumulation of lipid-laden MФ in the intima and (b) inhibiting both the reverse transdifferentiation of MΦ into vascular smooth muscle cells (VSMCs) and the differentiation of mesenchymal stem cells (MSCs) into VSMCs. Mice lacking fortilin^MΦ under genetically induced hypercholesterolemia (fortilin^KO-MΦ-HC) exhibit drastically less atherosclerosis in their aortae compared to wild-type (fortilin^WT-MΦ-HC) controls. Imaging mass cytometry reveals that the intima of fortilin^KO-MΦ-HC mice contains fewer MФ but more VSMCs than that of fortilin^WT-MФ-HC mice. Cell-based assays reveal that fortilin deficiency in MΦ augments low-density lipoprotein (LDL)-induced apoptosis, suppresses proliferation and foam cell formation, and boosts TGF-β1 production. Fortilin-deficient THP1 MΦ transdifferentiate into VSMCs, and their conditioned medium causes MSCs to differentiate toward VSMCs in a TGF-β1-dependent fashion. Together, these findings suggest that fortilin^MΦ plays a complex facilitative role in atherogenesis and represents a viable molecular target for the treatment of atherosclerosis.