MTUS1 silencing promotes E-selectin production through p38 MAPK-dependent CREB ubiquitination in endothelial cells. (December 2016)

• Record Type: Journal Article
• Authors: Wang, Yinfang; Dai, Xiuqin; Liu, Youbin; Li, Jinping; Liu, Zongjun; Yin, Peihao; Chen, Jingzhou; Wang, Ying; Wang, Nanping; Zhang, Peng
• Is Part Of: Journal of molecular and cellular cardiology. Volume 101(2016:Dec.)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-12
• Subjects: MTUS1 -- Endothelial cells -- E-selectin -- CREB -- p38 MAPK; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.10.012
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Endothelial cell activation is thought to be a key event in atherosclerosis. p38 mitogen-activated protein kinase (p38 MAPK) plays an important role in regulating pro-inflammatory cytokine production in endothelial cells (ECs), however, how p38 MAPK is controlled in EC activation remain unclear. In this study, we investigated the effect of mitochondrial tumor suppressor 1 (MTUS1) on p38 MAPK activation, cytokine induction and the underlying molecular mechanisms in ECs. Methods and results: Using qPCR and ELISA methods, we found that knockdown of MTUS1 led to a marked increase in the mRNA and protein expression of E -selectin (SELE) and monocyte chemotactic protein-1 in ECs, which is accompanied with increased phosphorylation of p38 MAPK (Thr180/Tyr182), MKK3/6 (Ser 189) and IκBα (Ser 32). Using luciferase reporter assay, we found that MTUS1 silencing also activated NF-κB transcriptional activity. The inhibition of p38 MAPK and NF-κB pathway was shown to abrogate MTUS1 silencing-induced cytokine expression in ECs. Furthermore, MTUS1 silencing induced p38 MAPK-dependent ubiquitination of cAMP-response element binding protein (CREB) which potentiated CREB-binding protein-mediated NF-κB p65 acetylation and binding to the promoter of the SELE gene. Conversely, adenovirus-mediated overexpression of MTUS1 inhibited p38 MAPK activation in ECs in vitro and in vivo . Importantly, decreased expression of MTUS1 and CREB, accompanied with induced activation of p38 MAPK were observed in aortas of apoE −/− mice after high-fat diet challenge. Conclusions: Our findings showed that MTUS1 regulates the p38 MAPK-mediated cytokine production in ECs. MTUS1 gene probably plays a protective role against pro-inflammatory response of ECs. Highlights: MTUS1 silencing induces expression of cytokine in endothelial cells. MTUS1 regulates expression of E -selectin in p38 MAPK dependent manner. MTUS1 silencing increases the ubiquitination of CREB in endothelial cells.