Disruption of SM22 Promotes Inflammation After Artery Injury via Nuclear Factor kappa B Activation

作者：Shen Jianbin; Yang Maozhou; Ju Donghong; Jiang Hong; Zheng Jian Pu; Xu Zhonghui; Li Li^*

来源：Circulation Research, 2010, 106(8): 1351-1362.

DOI：10.1161/CIRCRESAHA.109.213900

• VSMC
• SM22
• inflammation
• NF-kappa B
• ROS

Rationale: SM22 (or transgelin), an actin-binding protein abundant in vascular smooth muscle cells (VSMCs), is downregulated in atherosclerosis, aneurysm and various cancers. Abolishing SM22 in apolipoprotein E knockout mice accelerates atherogenesis. However, it is unclear whether SM22 disruption independently promotes arterial inflammation.
Objective: To investigate whether SM22 disruption directly promotes inflammation on arterial injury and to characterize the underlying mechanisms.
Methods and Results: Using carotid denudation as an artery injury model, we showed that Sm22 knockout (Sm22(-/-)) mice developed enhanced inflammatory responses with higher induction of proinflammatory genes, including Vcam1, Icam1, Cx3cl1, Ccl2, and Ptgs2. Higher expression of these genes was confirmed in primary Sm22(-/-) VSMCs and in PAC1 cells after Sm22 knockdown, whereas SM22 recapitulation in primary Sm22(-/-) VSMCs decreased their expression. NFKB2 was prominently activated in both injured carotids of Sm22(-/-) mice and in PAC1 cells after Sm22 knockdown and may mediate upregulation of these proinflammatory genes. As a NF-kappa B activator, reactive oxygen species (ROS) increased in primary Sm22(-/-) VSMCs and in PAC1 cells after Sm22 knockdown. ROS scavengers blocked NF-kappa B activation and induction of proinflammatory genes. Furthermore, Sm22 knockdown increased Sod2 expression and activated p47phox, reflecting contributions of mitochondria and NADPH oxidase to the augmented ROS production; this may result from actin and microtubule cytoskeletal remodeling.
Conclusions: Our findings show that SM22 downregulation can induce proinflammatory VSMCs through activation of ROS-mediated NF-kappa B pathways. This study provides initial evidence linking VSMC cytoskeleton remodeling with arterial inflammation. (Circ Res. 2010;106:1351-1362.)

• 出版日期2010-4-30