| First Author | Han S | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 137 |
| Pages | 82-92 | PubMed ID | 31639388 |
| Mgi Jnum | J:294347 | Mgi Id | MGI:6451246 |
| Doi | 10.1016/j.yjmcc.2019.10.003 | Citation | Han S, et al. (2019) Sam68 impedes the recovery of arterial injury by augmenting inflammatory response. J Mol Cell Cardiol 137:82-92 |
| abstractText | 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-alpha-induced NF-kappaB activation in fibroblasts. Here we sought to dissect the molecular mechanism by which Sam68 regulates NF-kappaB 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-alpha-induced expression of TNF-alpha, IL-1beta, and IL-6 and in the level of nuclear phospho-p65, indicating attenuated NF-kappaB 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-alpha treatment. Loss- and gain-of-function experiments suggest that Sam68 and FLNA are mutually dependent for NF-kappaB 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-kappaB signaling. |
