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

Abstract

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-κB activator, reactive oxygen species (ROS) increased in primary Sm22 −/− VSMCs and in PAC1 cells after Sm22 knockdown. ROS scavengers blocked NF-κB 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-κB pathways. This study provides initial evidence linking VSMC cytoskeleton remodeling with arterial inflammation.