Abstract
It is of great clinical significance to develop potential novel strategies to prevent cardio-cerebrovascular complications in patients with hyperlipidemia. Vascular Endothelial integrity and function play a key role in the prevention of cardio-cerebrovascular diseases. Endothelial progenitor cells (EPCs) can home to sites of ischemic injury and promote endothelial regeneration and neovascularization. Hypercholesterolemia impairs the function of EPC. The present study attempted to identify the effect of piperlongumine on EPCs’ angiogenic potential and cerebral ischemic injury in high-fat diet-fed (HFD-fed) mice. Here, we showed that treatment with low-does piperlongumine (0.25 mg/kg/day) for 8 weeks significantly improved EPCs function and reduced the cerebral ischemic injury (both infarct volumes and neurobehavioral outcomes) in HFD-fed mice. In addition, low-dose piperlongumine administration increased intracellular NO level and reduced intracellular O2 - level in EPCs of HFD-fed mice. Moreover, incubation with piperlongumine (1.0 μM, 24 h) reduced thrombospondin-1/2 (TSP-1/2, a potent angiogenesis inhibitor) expression levels in EPCs from HFD-fed mice, increased the therapeutic effect of EPC from HFD-fed mice on cerebral ischemic injury reduction and angiogenesis promotion in HFD-fed mice, and the donor derived EPCs homed to the recipient ischemic brain. In conclusion, low-dose piperlongumine can enhance EPCs’ angiogenic potential and protect against cerebral ischemic injury in HFD-fed mice. It is implied that treatment with low-dose piperlongumine might be a potential option to prevent ischemic diseases (including stroke) in patients with hyperlipidemia, and priming with piperlongumine might be a feasible way to improve the efficacy of EPC-based therapy for ischemic diseases.
Highlights
Dyslipidemia is an important risk factor for ischemic cerebrovascular disease (Kopin and Lowenstein, 2017)
To further interpret our findings, we checked whether the EPCmediated ischemic angiogenesis contributed to the protection of piperlongumine against cerebral ischemic injury in high-fat diet-fed (HFD-fed) mice and assess whether the incubation with piperlongumine increased the therapeutic effect of Endothelial progenitor cells (EPCs) from HFD-fed mice on cerebral ischemic injury reduction, 1×106 Bone Marrow-Derived EPCs (BM-EPCs) with or without piperlongumine incubation were systemically administrated to HFD-fed mice just after middle cerebral artery occlusion, and equivalent volume of vehicle (PBS) was administered to control mice (Figures 5, 6A) (Fan et al, 2010; Peng et al, 2018)
To further determine whether the EPC-mediated ischemic angiogenesis contributed to the protection of piperlongumine against cerebral ischemic injury in HFD-fed mice and assess whether the piperlongumine increased the therapeutic effect of EPCs from HFD-fed mice on cerebral ischemic injury reduction, 1×106 EPCs from HFD-fed mice with or without piperlongumine (1.0 μM, 24 h) incubation were systemically administrated to HFD-fed mice just after middle cerebral artery occlusion, and control HFD-fed mice received equal volume of vehicle (Figures 5, 6A)
Summary
Dyslipidemia is an important risk factor for ischemic cerebrovascular disease (Kopin and Lowenstein, 2017). It is of great clinical importance to develop new strategies to prevent cardio-cerebrovascular complications in patients with hyperlipidemia. It can be logically speculated that promoting EPC function and EPC-mediated ischemic angiogenesis may serve as a promising strategy to prevent cardio-cerebrovascular complications (such as coronary heart disease, stroke, and so on) in patients with hyperlipidemia. Piperlongumine’s function in preventing cardio-cerebrovascular complications in patients with hyperlipidemia has not been studied Based on these findings, this study sought to test the hypothesis that piperlongumine could reduce cerebral ischemic injury by promoting EPC-mediated angiogenesis in HFDfed mice. The present study, demonstrated for the first time that intraperitoneal low-dose piperlongumine injection for eight consecutive weeks significantly reduced cerebral ischemic injury in HFD-fed mice, which might be partly due to the promotion of EPC-mediated angiogenesis
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