SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B.

Pin Lv,Hai-Yue Wang,Mei Han,Ya-Juan Yin,Hao Xi,Yu-Hong Lv,Ning Wang,Yan Zhang,Hong-Chao Yang,Li Cao,Ning Chen,Peng Kong,Fan Zhang,Lei Nie,Yan-Ling Lin,Yong-Qing Dou,Rong Wang,Xiao-Ting Ma,Yi Wang

doi:10.1155/2021/5564884

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) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α−/− 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 (P < 0.01), and apoptosis of Sm22α−/− VSMCs was higher than that of WT VSMCs (P < 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 Sm22α−/− 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 Sm22α−/− VSMCs have a higher sensitivity to apoptosis.

Highlights

Vascular smooth muscle cells (VSMCs) are the main structural cells of blood vessels, and damage or death of VSMCs contributes to multiple vascular pathologies
Apoptosis of VSMCs has been associated with plaque rupture and aneurysm formation, which are thought to be a result of chronic inflammation [1]
Rescue of SM22α expression reduced the interaction of Sm22α-/- VSMCs with macrophages (Figure 2(d)), which displayed reduced transwell migration (Figure 2(e)) and expression of proinflammatory molecules in RAW264.7 cells under the same conditions (Figure 2(f)), suggesting that Sm22α-/- VSMCs are able to recruit and activate macrophages as SM22α was not expressed in WT mouse peritoneal macrophages and RAW264.7 cells

Summary

Introduction

Vascular smooth muscle cells (VSMCs) are the main structural cells of blood vessels, and damage or death of VSMCs contributes to multiple vascular pathologies. A more recent study using AAV carrying SM22α siRNA or SM22α overexpression plasmid in Ang II-perfused ApoE−/− mice confirmed that the causative role of SM22α deficiency in AAA formation occurs partly through enhancing vascular inflammation rather than increasing cell apoptosis [10]. These findings based on ApoE−/− mice with AAV-mediated knockdown or overexpression of SM22α in vivo are not enough to exclude a potential causative link between disturbed SM22α expression and VSMC apoptosis

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Results

Conclusion