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Knockdown of lncRNA PVT1 Inhibits Vascular Smooth Muscle Cell Apoptosis and Extracellular Matrix Disruption in a Murine Abdominal Aortic Aneurysm Model

  • Zhang, Zhidong (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Zou, Gangqiang (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Chen, Xiaosan (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Lu, Wei (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Liu, Jianyang (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Zhai, Shuiting (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital) ;
  • Qiao, Gang (Department of Vascular and Endovascular Surgery, Henan Provincial People's Hospital)
  • Received : 2018.04.11
  • Accepted : 2018.10.15
  • Published : 2019.03.31

Abstract

This study was designed to determine the effects of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) on vascular smooth muscle cell (VSMC) apoptosis and extracellular matrix (ECM) disruption in a murine abdominal aortic aneurysm (AAA) model. After injection of PVT1-silencing lentiviruses, AAA was induced in Apolipoprotein E-deficient ($ApoE^{-/-}$) male mice by angiotensin II (Ang II) infusion for four weeks. After Ang II infusion, mouse serum levels of pro-inflammatory cytokines were analysed, and aortic tissues were isolated for histological, RNA, and protein analysis. Our results also showed that PVT1 expression was significantly upregulated in abdominal aortic tissues from AAA patients compared with that in controls. Additionally, Ang II treatment significantly increased PVT1 expression, both in cultured mouse VSMCs and in AAA murine abdominal aortic tissues. Of note, the effects of Ang II in facilitating cell apoptosis, increasing matrix metalloproteinase (MMP)-2 and MMP-9, reducing tissue inhibitor of MMP (TIMP)-1, and promoting switching from the contractile to synthetic phenotype in cultured VSMCs were enhanced by overexpression of PVT1 but attenuated by knockdown of PVT1. Furthermore, knockdown of PVT1 reversed Ang II-induced AAA-associated alterations in mice, as evidenced by attenuation of aortic diameter dilation, marked adventitial thickening, loss of elastin in the aorta, enhanced aortic cell apoptosis, elevated MMP-2 and MMP-9, reduced TIMP-1, and increased pro-inflammatory cytokines. In conclusion, our findings demonstrate that knockdown of lncRNA PVT1 suppresses VSMC apoptosis, ECM disruption, and serum pro-inflammatory cytokines in a murine Ang II-induced AAA model.

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Fig. 1. lncRNA PVT1 was upregulated in abdominal aortic tissues from AAA patients and ApoE-/- AAA models.

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Fig. 2. Relative PVT1 expression in Ang IIinduced VSMCs and the effect of PVT1 expression on Ang II-induced apoptosis.

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Fig. 3. Effects of PVT1 expression on ECM degradation and phenotype switching of Ang II-induced VSMCs.

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Fig. 4. sh-PVT1 attenuated Ang II-induced AAA in mice.

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Fig. 5. sh-PVT1 attenuated Ang II-induced PVT1 expression, ECM degradation, and inflammation in mice.

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