SM22 (or transgelin), an actin-binding protein abundant in vascular smooth muscle cells (VSMC), 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.
To investigate whether SM22 disruption directly promotes inflammation upon 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 pro-inflammatory 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, while SM22 recapitulation in primary Sm22−/− VSMCs decreased their expression. NF-κB pathways were prominently activated in both injured carotids of Sm22−/− mice and in PAC1 cells after Sm22 knockdown and may mediate upregulation of these pro-inflammatory 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 pro-inflammatory 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.
Our findings show that SM22 downregulation in VSMCs can independently promote arterial inflammation through activation of ROS-mediated NF-κB pathways. This study provides initial evidence linking VSMC cytoskeleton remodeling with arterial inflammation.