Molecular Biology Reports

, Volume 39, Issue 1, pp 285–293

Simvastatin augments the efficacy of therapeutic angiogenesis induced by bone marrow-derived mesenchymal stem cells in a murine model of hindlimb ischemia

  • Yuqing Zhang
  • Rusheng Zhang
  • Yong Li
  • Guoping He
  • Dingguo Zhang
  • Fumin Zhang
Article

DOI: 10.1007/s11033-011-0737-y

Cite this article as:
Zhang, Y., Zhang, R., Li, Y. et al. Mol Biol Rep (2012) 39: 285. doi:10.1007/s11033-011-0737-y

Abstract

Many studies showed beneficial effects of either statin or bone marrow-derived mesenchymal stem cells (MSC) treatment in ischemic disease. In an attempt to further improve postischemic tissue repair, we investigated the effect of a local administration of MSC, in the presence or not of low-dose simvastatin, on angiogenesis and functional recovery in a mouse model of hindlimb ischemia. In vitro, the proliferation, migration, apoptosis, and tube formation of bone marrow MSC derived from transgenic mice expressing green fluorescent protein (GFP) were detected in the presence or not of 0.01 μmol/l simvastatin, respectively. In vivo, immediately after hindlimb ischemia, the mice were divided into four groups, namely control, MSC, statin, and statin-MSC, and received a single local injection of MSC (2 × 106 cells) and/or a repeated gavages’ administration of simvastatin (0.2 mg/kg) for 21 days. The blood flow was measured by laser Doppler imaging, the capillary density was detected by alkaline phosphatase staining and, the MSC differentiation was assessed by immunofluorescent staining at 21 days after the ischemia. In vitro, the MSC proliferation rate, migration ability and tube formation number were increased significantly in simvastatin group relative to control group. Whereas, the H2O2 induced-apoptosis was inhibited significantly in simvastatin group relative to control group. In vivo, hindlimb blood reperfusion was significantly improved (MSC 0.55 ± 0.08, statin 0.57 ± 0.05, vs. control 0.47 ± 0.07, P < 0.05) and capillary density was obviously higher at day 21 post-ischemia by Laser Doppler Imaging in the MSC group and the Statin group when compared with control group. The combined use of statin and MSC further improved revascularization (perfusion ratio of 0.70 ± 0.09; P < 0.001 verse other groups) and resulted in the highest capillary density (P < 0.05 vs. all other groups). GFP-labeled transplanted cells were more frequently observed in the Statin-MSC group than in the MSC group (6.8 ± 0.5–3.1 ± 0.7, P < 0.05). Low-dose simvastatin could act in a synergistic way with MSC to potentiate the functional neovascularization in a mouse model of hind limb ischemia.

Keywords

Hindlimb ischemia Statin Bone marrow stem cell 

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Yuqing Zhang
    • 1
  • Rusheng Zhang
    • 2
  • Yong Li
    • 3
  • Guoping He
    • 3
  • Dingguo Zhang
    • 4
  • Fumin Zhang
    • 5
  1. 1.Department of CardiologyThe Affiliated Jiangning Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of CardiologyJiangsu Provincial Hospital of Traditional Chinese MedicineNanjingChina
  3. 3.Department of CardiologyThe Affiliated Wujin Hospital of Jiangsu UniversityChangzhouChina
  4. 4.Research Center for Bone and Stem CellsNanjing Medical UniversityNanjingChina
  5. 5.Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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