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Low shear stress inhibits endothelial mitophagy via caveolin-1/miR-7-5p/SQSTM1 signaling pathway

  • Weike Liu
    Affiliations
    Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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  • Huajing Song
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
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  • Jing Xu
    Affiliations
    Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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  • Yuqi Guo
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
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  • Chunju Zhang
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
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  • Yanli Yao
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
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  • Hua Zhang
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China

    Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
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  • Zhendong Liu
    Affiliations
    School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China

    Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
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  • Yue-Chun Li
    Correspondence
    Corresponding author. Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109, Xueyuan Road, Wenzhou, Zhejiang, 325000, China.
    Affiliations
    Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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      Highlights

      • Low shear stress inhibits endothelial mitophagy.
      • Caveolin-1 and miR-7-5p play an important role in the process of low shear stress inhibiting endothelial mitophagy.
      • Endothelial mitophagy associates with oxidative stress reaction and endothelial dysfunction.

      Abstract

      Background and aims

      Mitophagy plays a crucial role in mitochondrial homeostasis and is closely associated with endothelial function. However, the mechanism underlying low blood flow shear stress (SS), detrimental cellular stress, regulating endothelial mitophagy is unclear. This study aimed to investigate whether low SS inhibits endothelial mitophagy via caveolin-1 (Cav-1)/miR-7-5p/Sequestosome 1 (SQSTM1) signaling pathway.

      Methods

      Low SS in vivo modeling was induced using a perivascular SS modifier implanted in the carotid artery of mice. In vitro modeling, low and physiological SS (4 and 15 dyn/cm2, respectively) were exerted on human aortic endothelial cells using a parallel plate chamber system.

      Results

      Compared with physiological SS, low SS significantly inhibited endothelial mitophagy shown by down-regulation of SQSTM1, PINK1, Parkin, and LC 3II expressions. Deficient mitophagy deteriorated mitochondrial dynamics shown by up-regulation of Mfn1 and Fis1 expression and led to decreases in mitochondrial membrane potential. Cav-1 plays a bridging role in the process of low SS inhibiting mitophagy. The up-regulated miR-7-5p expression induced by low SS was suppressed after Cav-1 was silenced. The results of dual-luciferase reporter assays showed that miR-7-5p targeted inhibiting the SQSTM1 gene. Oxidative stress reaction shown by the elevation of reactive oxygen species and O2●— and endothelial dysfunction by the decrease in nitric oxide and the increase in macrophage chemoattractant protein-1 were associated with the low SS inhibiting endothelial mitophagy process.

      Conclusions

      Cav-1/miR-7-5p/SQSTM1 signaling pathway was the mechanism underlying low SS inhibiting endothelial mitophagy that involves mitochondrial homeostasis impairment and endothelial dysfunction.

      Graphical abstract

      Keywords

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