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-kB activator, reactive oxygen species (ROS) increased in primary Sm22-/- VSMCs and in PAC1 cells after Sm22 knockdown. ROS scavengers blocked NF-kB 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. © 2010 American Heart Association, Inc.