RESUMEN
OBJECTIVE: Salsalate is a dimeric form of salicylic acid that has been shown to have anti-inflammatory activity and to reduce glucose levels, insulin resistance, and cytokine expression. However, the effect of salsalate on vascular injury has not been determined. The objective of this study is to investigate the effect of salsalate on vascular injury and repair in a rat model of carotid artery balloon catheter injury. RESEARCH DESIGN AND METHODS: Salsalate treatment was started in female Zucker fatty rats (insulin resistant) 1 week before carotid artery balloon catheter injury and continued for 21 days, at which time the animals were killed and studied. RESULTS: Treatment with salsalate significantly decreased the intima-to-media ratio and upregulated the expression of aortic endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (ser 1177), and manganese superoxide dismutase (MnSOD) and reduced serum interleukin (IL)-6 with concomitant downregulation of nuclear factor (NF) κB subunit p65 and vascular endothelial growth factor (VEGF) expression in the balloon-injured carotid artery of female Zucker fatty rats. CONCLUSIONS: The present study shows that salsalate treatment decreases vascular damage caused by balloon catheter injury in female Zucker fatty rats. The beneficial effect of salsalate on vascular injury was associated with upregulation of eNOS, p-eNOS, and MnSOD, which reduce oxidative stress and have anti-inflammatory properties, as evidenced by reduction in serum IL-6 and the downregulation of VEGF and NFκB, which promote inflammation without changing glucose levels. These results suggest that salsalate may be useful in reducing vascular injury and restenosis following interventional revascularization procedures.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Salicilatos/uso terapéutico , Animales , Western Blotting , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/etiología , Traumatismos de las Arterias Carótidas/patología , Cateterismo/efectos adversos , Femenino , Inmunohistoquímica , Óxido Nítrico Sintasa de Tipo III/genética , Ratas , Ratas Zucker , Superóxido Dismutasa/genética , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We studied the effect of a synthetic GLP-1 receptor agonist, exenatide, a drug approved for the treatment of type 2 diabetes, on the recovery from vascular injury in Zucker (non-diabetic) fatty rats. Exenatide 5.0 microg/kg per day or saline was administered for seven days before, and 21 days after balloon catheter mediated carotid injury. A pair feeding experiment helped differentiate between the drug itself and the known effects of the drug on decreased food intake. Body weight and glucose (weekly), carotid artery I/M ratio, aortic protein eNOS and NFkappaB-p65 were measured. Body weight gain in exenatide rats was significantly lower (53+/-5 vs. 89+/-8 g) than controls. Blood glucose did not change significantly. The I/M ratio in the exenatide group was 0.2+/-0.1 vs. 0.9+/-0.1 in controls (p<0.05). The expression of aortic eNOS was unchanged in exenatide treated rats and a small decrease seen in NFkappaB-p65 expression was not statistically significant. We conclude that exenatide attenuates intimal hyperplasia following balloon catheter induced vascular injury independently of glucose regulation and food intake. Our findings provide additional support for cardiovascular benefits of exenatide, especially in obese and pre-diabetic patients. Further research is needed to elucidate the mechanism underlying these effects.