SM22<i>α</i> Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage‐Derived circRasGEF1B

Abstract

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22<i>α</i> prevents AAA formation through suppressing NF-<i>κ</i>B activation. However, the role of SM22<i>α</i> in VSMC apoptosis is controversial. Here, we identified that SM22<i>α</i> loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22<i>α</i> enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by <i>Sm22α</i> ^-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM (<i>P</i> < 0.01), and apoptosis of <i>Sm22α</i> ^-/- VSMCs was higher than that of WT VSMCs (<i>P</i> < 0.001). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in <i>Sm22α</i> ^-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas <i>Sm22α</i> ^-/- VSMCs have a higher sensitivity to apoptosis.