SAMD1 Distribution Patterns in Mouse Atherosclerosis Models Suggest Roles in LDL Retention, Antigen Presentation, and Cell Phenotype Modulation
The theory that lesions formed by retention of circulating LDL can then progress to complicated atherosclerotic lesions has been a subject of debate, as has the mechanism of retention. In earlier work, we identified SAMD1, a protein expressed by intimal smooth muscle cells in human lesions that appears to irreversibly bind apoB-Lps in extracellular matrix near the lumen. We hypothesized this binding could contribute to the formation of lesions in mice, and that inhibiting binding could reduce lesion growth. In mouse models of atherosclerosis, we found that SAMD1 binds LDL; that SAMD1/apoB complex is ingested by intimal cells; and that recognizable epitopes of the SAMD1/apoB complex survive some degree of catabolism in foam cell. These data appear to support the SAMD1/LDL retention hypothesis of lesion growth. Despite apparently irreversible binding of human LDL to full-length human SAMD1, efficient anti-SAMD1-antibody inhibitors were created. In vivo lesion targeting of inhibitors was demonstrated by MRI, ultrasound, and ex vivo microscopy. However, only non-statistically significant reductions in spontaneous lesion size in apoE-/- mice were seen after 12 weeks of treatment with PEG-fab inhibitors of SAMD1/LDL binding. In contrast, these inhibitors substantially reduced LDL retention in carotid injury lesions in apoE-/- and LDLR-/- mice 7 days after injury. The most obvious difference between injury lesions and early spontaneous lesions is the presence of numerous smooth muscle cells and associated extracellular matrix in the injury lesions. Thus, SAMD1 may be involved in retention of apoB-Lps in mouse lesions, but not until smooth muscle cells have entered the intima. In addition, SAMD1 is seen throughout arteries in changing patterns that suggest broader and more complicated roles in atherosclerosis.