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B DKK3 Stabilises Atherosclerotic Plaque via Promoting Vascular Progenitor and Fibroblast Differentiation to Smooth Muscle Cells
  1. Eirini Karamariti1,
  2. Chungang Zhai2,
  3. Baoqi Yu1,
  4. Christof Niehrs3,
  5. Yanhua Hu1,
  6. Cheng Zhang2,
  7. Qingbo Xu1
  1. 1Cardiovascular Division, King’s College London BHF Centre, London, UK
  2. 2The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, China
  3. 3Institute of Molecular Biology (IMB), Mainz, Germany

Abstract

Atherosclerosis, a chronic condition that can be converted into an acute clinical event caused by plaque rupture and thrombosis, has been the primary cause of mortality and morbidity worldwide. Dickkopf 3 (DKK3), a 36-kD secreted glycoprotein, has a role in cell differentiation, but little is known about its involvement in vascular disease. In the present study, we utilised a murine model of atherosclerosis (ApoE-/-) in conjunction with DKK3-/- to assess the effects of DKK3 on plaque stability.

We found that the absence of DKK3 leads to vulnerable unstable atherosclerotic plaques, due to a reduced number of smooth muscle cells (SMCs) and reduced matrix protein deposition, as well as increased haemorrhage and macrophage infiltration. Using a cell linear tracing method, vascular progenitors and fibroblasts from SM22-LacZ transgenic mice were isolated and applied to the adventitial side of injured femoral arteries resulting in migration of both types of cells to the intima. Upon migration the cells displayed beta-gal positivity, indicating SMC differentiation.

Further in vitro studies revealed that DKK3 can induce differentiation of Sca1+ vascular progenitors and fibroblasts into SMCs via activation of the TGFβ/ATF6 and Wnt signalling pathways. Finally, we assessed the therapeutic potential of DKK3 in mouse and rabbit models and found that DKK3 increases atherosclerotic plaque stability via an increase in SMC numbers and reduced vascular inflammation. Cumulatively, we provide the first evidence that DKK3 is a potent SMC differentiation factor, which may have a therapeutic effect in reducing acute haemorrhagic conditions through promotion of atherosclerotic plaque stability.

  • Plaque stability
  • Dkk3
  • smooth muscle cells

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