Abstract
ObjectivesWe postulated that combining high-dose simvastatin with bone marrow derived-mesenchymal stem cells (MSCs) delivery may give better prognosis in a mouse hindlimb ischemia model.MethodsMouse hindlimb ischemia model was established by ligating the right femoral artery. Animals were grouped (n = 10) to receive local injection of saline without cells (control and simvastatin groups) or with 5 × 106 MSCs (MSCs group).Animals received either simvastatin (20 mg/kg/d, simvastatin and combination groups) or saline(control and MSCs group) gavages for continual 21 days. The blood flow was assessed by laser Doppler imaging at day 0,10 and 21 after surgery, respectively. Ischemic muscle was harvested for immunohistological assessments and for VEGF protein detection using western blot assay at 21 days post-surgery. In vitro, MSCs viability was measured by MTT and flow cytometry following culture in serum-free medium for 24 h with or without simvastatin. Release of VEGF by MSCs incubated with different doses of simvastatin was assayed using ELISA.ResultsCombined treatment with simvastatin and MSCs induced a significant improvement in blood reperfusion, a notable increase in capillary density, a highest level of VEGF protein and a significant decrease in muscle cell apoptosis compared with other groups. In vitro, simvastatin inhibited MSCs apoptosis and increased VEGF release by MSCs.ConclusionsCombination therapy with high-dose simvastatin and bone marrow-derived MSCs would augment functional neovascularization in a mouse model of hindlimb ischemia.
Highlights
Peripheral arterial disease (PAD) is one of the most common clinical manifestations of atherosclerosis, which affects a significant number of individuals
We investigated whether the combination therapy with high-dose simvastatin administration and mesenchymal stem cells (MSCs) transplantation could augment functional neovascularization in a mouse model of hind limb ischemia
Combination therapy increases blood perfusion To determine whether simvastatin or MSCs treatment could stimulate the blood reperfusion in ischemic limb, mice were treated with simvastatin or MSCs or vehicle, the blood reperfusion was examined at day 0, 10 and 21 after the treatment by LDPI
Summary
Peripheral arterial disease (PAD) is one of the most common clinical manifestations of atherosclerosis, which affects a significant number of individuals. It represents an important cause of disability and is associated with elevated cardiovascular morbidity and mortality[1]. Recent studies have demonstrated that statins could protect against ischemic injury of the heart [9]and stimulate angiogenesis in ischemic limbs of normocholesterolemic animals [10]. Both in vitro and in vivo studies have suggested a biphasic and dose-dependent effect of statins on angiogenesis [11]. We investigated whether the combination therapy with high-dose simvastatin administration and MSCs transplantation could augment functional neovascularization in a mouse model of hind limb ischemia
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