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Low shear stress damages endothelial function through STAT1 in endothelial cells (ECs)

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Abstract

Low shear stress (LSS) occurs in areas where atherosclerosis is prevalent. Many studies have revealed that signal transducer and activator of transcription 1 (STAT1) plays a significant role in cardiovascular disease. Nonetheless, the mechanism underlying the connection between STAT1 and LSS is not fully understood. The purpose of this study was to investigate the link between LSS and STAT1 in endothelial cells (ECs). Monolayer endothelial cells were stimulated or not stimulated by LSS. Protein expression and phosphorylation levels were determined by western blotting. Immunofluorescence was used to compare the protein expression differences in bifurcated and non-bifurcated human coronary arteries. Endothelial function was assessed by using a dihydroethidium assay, real-time PCR, western blotting and nitric oxide (NO)-sensitive fluorophore. Results showed that STAT1 played a key role in LSS-induced endothelium damage. Firstly, LSS activated STAT1, as evidenced by LSS-induced STAT1 (Tyr701) phosphorylation in ECs in vitro and the increased intimal STAT1 expression at bifurcation of human coronary arteries. Secondly, LSS-induced STAT1 phosphorylation was positively regulated by inhibitor of nuclear factor kappa-B kinase ε (IKKε). Additionally, LSS-promoted inflammatory factor expression was markedly reversed by silencing STAT1 (siSTAT1). LSS also increased reactive oxygen species (ROS) level and decreased endogenous NO release: however, siSTAT1 reversed these adverse effects through upregulating the antioxidant gene heme oxygenase-1(HO-1) and downregulating endothelial nitric oxide synthase (eNOS) Thr495 phosphorylation. According to our results, LSS-mediated EC injury may be associated with the activation of STAT1. Strategies designed to reduce STAT1 expression or inhibit STAT1 activation may be effective approaches for reducing the incidence of atherosclerosis.

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Funding

We acknowledge the National Natural Science Foundation of China (NSFC-81770441 and NSFC-81770342) for supporting this study.

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Author notes

  1. Linlin Zhu, Feng Wang and Hongfeng Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

    Linlin Zhu, Feng Wang, Junjie Zhang & Shaoliang Chen

  2. Department of intensive Care Unit, Affiliated People’ Hospital of Jiangsu University, Zhenjiang, China

    Hongfeng Yang

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  1. Linlin Zhu
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Contributions

ZLL and WF performed the in vitro experiment, analysed the echo data and drafted the manuscript. YHF aided in collecting tissues and analysing the data. WF analysed the data and edited the manuscript. ZJJ and CSL designed and oversaw the study and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junjie Zhang or Shaoliang Chen.

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Key points

• Low shear stress activates IKKε-STAT1 signalling pathway.

• STAT1 is involved in endothelial inflammation in response to LSS.

• STAT1 contributes to LSS-induced increased ROS level and decreased NO release.

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Zhu, L., Wang, F., Yang, H. et al. Low shear stress damages endothelial function through STAT1 in endothelial cells (ECs). J Physiol Biochem 76, 147–157 (2020). https://doi.org/10.1007/s13105-020-00729-1

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  • DOI: https://doi.org/10.1007/s13105-020-00729-1

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