Novel Atheroma-specific Atheroprotective Factor Promotes VSMC Pro-survival Signaling

Cardiovascular disease, the leading cause of death in the United States, is primarily driven by atherosclerosis. In recent years, studies have focused on identification of naturally expressed, atheroprotective genes for use in delaying development of or preventing complications from atherosclerosis. To this end, we previously identified SPRR3 (small proline rich protein 3) as a gene specifically upregulated in vascular smooth muscle cells (VSMCs) of atheroma versus healthy arterial tissue of humans and mice. In the present study, we generated ApoE-null mice lacking SPRR3, which displayed significantly increased atheroma burden compared with ApoE-null controls. To determine the cellular driver(s) of this phenotype, we investigated SPRR3-dependent changes in bone marrow-derived cells, endothelial cells (ECs), and VSMCs. Bone marrow transplant of SPRR3-expressing cells into SPRR3-/-ApoE-/- recipients failed to rescue atheroma burden. Similarly, no change was observed in SPRR3-deficient versus control ECs. However, apoptosis was significantly reduced in SPRR3-overexpressing VSMCs in vitro. A positive association was also observed between SPRR3 expression and PI3K/Akt activity in VSMCs. The SPRR3-dependent survival advantage observed in SPRR3-overexpressing cells was lost following treatment with PI3K/Akt pathway inhibitor. Our data indicate that SPRR3 protects the atheroma from VSMC loss by promoting survival signaling in lesion VSMCs, thereby modulating atherosclerosis development. As the first identified atheroma-specific VSMC pro-survival factor, SPRR3 represents a potential target for lesion-specific modulation of VSMC survival to inhibit plaque progression.