Abstract
BackgroundDiabetes exacerbates abnormal vascular smooth muscle cell (VSMC) accumulation in response to arterial wall injury. Vinpocetine has been shown to improve vascular remolding; however, little is known about the direct effects of vinpocetine on vascular complications mediated by diabetes. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism.Materials and MethodsNondiabetic and diabetic rats were subjected to balloon injury of the carotid artery followed by 3-week treatment with either vinpocetine (10 mg/kg/day) or saline. Morphological analysis and proliferating cell nuclear antigen (PCNA) immunostaining were performed on day 21. Rat VSMCs proliferation was determined with 5-ethynyl-20-deoxyuridine cell proliferation assays. Chemokinesis was monitored with scratch assays, and production of reactive oxygen species (ROS) was assessed using a 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) flow cytometric assay. Apoptosis was detected by annexin V-FITC/PI flow cytometric assay. Cell signaling was assessed by immunblotting.ResultsVinpocetine prevented intimal hyperplasia in carotid arteries in both normal (I/M ratio: 93.83 ± 26.45% versus 143.2 ± 38.18%, P<0.05) and diabetic animals (I/M ratio: 120.5 ± 42.55% versus 233.46 ± 33.98%, P<0.05) when compared to saline. The in vitro study demonstrated that vinpocetine significantly inhibited VSMCs proliferation and chemokinesis as well as ROS generation and apoptotic resistance, which was induced by high glucose (HG) treatment. Vinpocetine significantly abolished HG-induced phosphorylation of Akt and JNK1/2 without affecting their total levels. For downstream targets, HG-induced phosphorylation of IκBα was significantly inhibited by vinpocetine. Vinpocetine also attenuated HG-enhanced expression of PCNA, cyclin D1 and Bcl-2.ConclusionsVinpocetine attenuated neointimal formation in diabetic rats and inhibited HG-induced VSMCs proliferation, chemokinesis and apoptotic resistance by preventing ROS activation and affecting MAPK, PI3K/Akt, and NF-κB signaling.
Highlights
Diabetes mellitus increases the risk of atherosclerosis and the incidence of complications from atherosclerosis such as coronary artery disease, stroke and so on
The in vitro study demonstrated that vinpocetine significantly inhibited vascular smooth muscle cell (VSMC) proliferation and chemokinesis as well as reactive oxygen species (ROS) generation and apoptotic resistance, which was induced by high glucose (HG) treatment
The final body weights of rats were lower in the diabetic group than the control group, but they were not influenced by the 3-week treatment with vinpocetine (10 mg/kg/day IP)
Summary
Diabetes mellitus increases the risk of atherosclerosis and the incidence of complications from atherosclerosis such as coronary artery disease, stroke and so on. Revascularization through balloon dilatation or stent placemet would ameliorate coronary artery disease, patients with diabetes mellitus experienced worse outcomes than non-diabetic patients [2]. Abnormal neointimal hyperplasia is considered the predominant mechanism in the pathogenesis of postangioplasty restenosis [4]. Even with the application of drug eluting stents (DES), the adjusted risk of restenosis was higher in patients with DM than in patients without DM (RR: 1.23, 95% confidence interval [CI]: 1.10 to 1.37) [3]. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism
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