Sam68 impedes the recovery of arterial injury by augmenting inflammatory response

Shuling Han, Shiyue Xu, Junlan Zhou, Aijun Qiao, Chan Boriboun, Wenxia Ma, Huadong Li, Dauren Biyashev, Liu Yang, Eric Zhang, Qinghua Liu, Shayi Jiang, Ting C. Zhao, Prasanna Krishnamurthy, Chunxiang Zhang, Stéphane Richard, Hongyu Qiu, Jianyi Zhang, Gangjian Qin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Objective: The role of Src-associated-in-mitosis-68-kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 promotes TNF-α–induced NF-κB activation in fibroblasts. Here we sought to dissect the molecular mechanism by which Sam68 regulates NF-κB signaling and its functional significance in vascular injury. Approach and results: The endothelial denudation injury was induced in the carotid artery of Sam68-null (Sam68−/−) and WT mice. Sam68−/− mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced macrophage infiltration and lowered expression of pro-inflammatory cytokines in the injured vessels. Remarkably, the ameliorated vascular remodeling was recapitulated in WT mice after receiving transplantation of bone marrow (BM) from Sam68−/− mice, suggesting the effect was attributable to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α–induced expression of TNF-α, IL-1β, and IL-6 and in the level of nuclear phospho-p65, indicating attenuated NF-κB activation; and these results were confirmed in peritoneal and BM-derived macrophages of Sam68−/− vs. WT mice. Furthermore, co-immunoprecipitation and mass-spectrometry identified Filamin A (FLNA) as a novel Sam68-interacting protein upon TNF-α treatment. Loss- and gain-of-function experiments suggest that Sam68 and FLNA are mutually dependent for NF-κB activation and pro-inflammatory cytokine expression, and that the N-terminus of Sam68 is required for TRAF2-FLNA interaction. Conclusions: Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery by interacting with FLNA to stabilize TRAF2 on the cytoskeleton and consequently potentiate NF-κB signaling.

Original languageEnglish (US)
Pages (from-to)82-92
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
StatePublished - Dec 2019


  • Filamin a
  • Inflammation
  • Macrophage
  • NF-κB
  • Restenosis
  • Sam68
  • TNF-α

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Molecular Biology


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