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Circ Res. 2010 Apr 30;106(8):1351-62. doi: 10.1161/CIRCRESAHA.109.213900. Epub 2010 Mar 11.

Disruption of SM22 promotes inflammation after artery injury via nuclear factor kappaB activation.

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1
Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA.

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

PMID:
20224039
PMCID:
PMC2896867
DOI:
10.1161/CIRCRESAHA.109.213900
[Indexed for MEDLINE]
Free PMC Article

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