[Show abstract][Hide abstract]ABSTRACT: The 5-lipoxygenase catalyzed formation of leukotriene lipid mediators is a mediator for inflammatory response in arteries. The present study investigated the relationship between atorvastatin and the 5-lipoxygenase pathway in an atherosclerotic rabbit model.
Thirty male New Zealand White Rabbits were randomized into negative control, positive control and atorvastatin groups. At week 4, the rabbits were subjected to carotid balloon-dilation injury or carotid balloon-dilation injury, followed by treatment with atorvastatin. At week 12, all the animals were sacrificed. Plasma lipids, LTD(4), and 15-epi-lipoxin A(4) were measured using the enzymatic endpoint method and ELISA, respectively. RT-PCR was performed to detect the gene expression of 5-lipoxygenase-activating protein and cysLT1R in rabbit carotid arteries. Finally, histological analysis was used to evaluate the pathophysiological changes of rabbit carotid arteries.
The results showed atorvastatin markedly lowered serum lipids and LTD(4) levels compared with the control group. Similarly, mRNA expression of 5-lipoxygenase-activating protein and cysLT1R was significantly inhibited by atorvastatin. Decreased carotid plaque instability was evident in atorvastatin-treated animals, as demonstrated by a thickened elastic layer, less neointima hyperplasia and macrophage proliferation.
Atorvastatin may stabilize carotid plaque by regulating the 5-lipoxygenase pathway in atherosclerotic rabbits and delay the progression of atherosclerosis by exerting anti-inflammatory effects.
[Show abstract][Hide abstract]ABSTRACT: Matrix metalloproteinases (MMPs) play important roles in the development and destabilization of atherosclerotic plaques. It is known that montelukast inhibits neointimal hyperplasia. However, the underlying mechanisms for the inhibitory effects of montelukast on neointimal formation have been poorly defined.
Thirty-six male New Zealand White rabbits were randomized as normal control, placebo (0.9% NaCl, 1.5 ml/kg/day, via intraperitoneal injection), atorvastatin (atorvastatin, 1.5 mg/kg/day, orally) and montelukast groups (montelukast, 1.5 mg/kg/day, via intraperitoneal injection). Atherosclerosis was induced by balloon-injury and high-cholesterol (HC) diet. Serum lipids were measured at 0, 8 and 12 weeks. After 12 weeks, the rabbits were sacrificed and histopathological changes examined. Immunohistochemistry and reverse transcription-polymerase chain reaction were used to measure the expression of MMP-2 and MMP-9 in the plaques.
It was found that montelukast reduced neointimal formation, decreased macrophage accumulation, and increased smooth muscle cells. It also attenuated the expression of MMP-2 and MMP-9 in atherosclerotic plaques, but it had no effect on plasma lipid levels.
These data indicate that montelukast inhibits neointimal hyperplasia in association with decreased expression of MMP-2 and MMP-9 independent of plasma lipid levels in atherosclerotic plaques after vascular injury in hyperlipidemic rabbits.
No preview · Article · Dec 2009 · Cardiovascular Drugs and Therapy
[Show abstract][Hide abstract]ABSTRACT: Atherosclerosis is characterized by inflammatory responses of the arterial wall to "injury", which is prominently driven by inflammatory mediators. Montelukast, a selective CysLT1 receptor antagonist, has potent anti-inflammatory effects in diverse animal models. However, the role of montelukast in regulating inflammatory progression of atherosclerosis has not been elucidated. Therefore, we investigated the effect of montelukast on atherosclerosis compared with that of atorvastatin. Twenty-six male New Zealand White rabbits were randomized into four groups including a negative control group. The rabbits were fed a normal diet or an atherogenic diet for 12 weeks. The rabbits, except the negative control group, received right carotid artery balloon-injury 2 weeks after initiation of the atherogenic diet. Animals were then treated with montelukast (1mg/kg/day), atorvastatin (1.5mg/kg/day) or placebo for 4 weeks, respectively. At the end of the treatment, animals were killed and carotids were dislodged and detected. The results indicated that the placebo group had significant progression of atherosclerosis compared with the negative control group. In contrast, montelukast or atorvastatin treated rabbits showed a significant reduction of neointima, decreased macrophage content, increased SMC content and inhibited expression of MCP-1. Between two drugs, there were no significant differences in reducing neointima and decreasing the level of MCP-1. However, montelukast had no influence on plasma lipids, while atorvastatin down-regulated the levels of TC, TG and LDL. These results suggest that montelukast produces anti-atherogenic effects unrelated to plasma lipid modulation but related to MCP-1 down regulation.
[Show abstract][Hide abstract]ABSTRACT: Objective: To study the effect of atorvastatin on matrix metalloproteinase 9 (MMP-9) expression in the upstream shoulder (proximal end) of aortic atherosclerotic plaques in rabbits. Methods: Thirty male New Zealand rabbits were randomized into normal control group n = 9), high-lipid diet group (n = 11) and atorvastatin group (n = 10). An aortic atherosclerotic model was induced by high-lipid diet in the last two groups. From the ninth week, the high-lipid diet group rabbits were administered starch 1.5 mg/kg body weight per day, and the rabbits of atorvastatin group were administered atorvastatin 1.5 mg/kg body weight per day. After the rabbits were killed, the gross specimen of aorta was observed, and the rabbits whose intimal hyperplasia complicated with the formation of atherosclerotic plaque were regarded as the successful induction of the model. The percentage of macrophage and smooth muscle cell positive area in the upstream shoulder of plaques and the expression of MMP-9 were detected by immunohistochemistry methods. Results: The formation of neointima was seen in aorta in the high-lipid diet and atorvastation groups, the ratios of intima-media thickness were 1.41 ± 0.34 and 0.63 ± 0.12, respectively. The distribution sites of macrophages in the plaques were in concordance with the region of positive expression of MMP-9, and they were all assembled at the upstream shoulder of the plaques. As compared with the high-lipid diet group, atorvastatin reduced aggregation of macrophages significantly (the percentages of positive areas were 26.5% ± 4.3% and 12.4% ± 1.5%, respectively) and expression of MMP-9 (the values of optical density were 0.081 ± 0.014 and 0.022 ± 0.004, respectively) in the upstream shoulders of the aortic plaques. There were significant differences between the two groups (P<0.01). The percentages of positive areas of smooth muscle cells in the high-lipid diet and atorvastatin groups were 47.2% ± 12.3% and 50.4% ± 10.8%, respectively. There were no significant differences between the two groups (P > 0.05). Conclusions: The macrophages in the atherosclerotic plaque and the expressions of MMP-9 are mainly in the upstream shoulder. Atorvastatin may significantly reduce the aggregation of macrophages and the expression of MMP-9 in this area.
No preview · Article · Aug 2008 · Chinese Journal of Cerebrovascular Diseases
[Show abstract][Hide abstract]ABSTRACT: Objective: To investigate the pathogenesis of middle cerebral artery(MCA) stenosis and occlusion caused cerebral infarction by a contrast study on atherosclerotic stenosis and occlusion of the main stem of MCA caused cerebral infarction in different MCA blood supplied areas and to provide evidence for the relative therapeutic strategies. Methods: The clinical and imaging data of 61 patients with fresh cerebral infarction caused by atherosclerotic MCA stenosis(stenosis >50%) and occlusion were analyzed retrospectively. The patients were divided into stenosis group(n = 27) and occlusion group(n = 34). The locations of cerebral infarction were determined and compared according to the results of MRI diffusion-weighted imaging(DWI) within one week after onset. Results: Single infarction in the stenosis and occlusion groups were 15(55.6%) and 8(23.5%) patients, respectively, and the multiple infarctions in the two groups were 12(44.4%) and 26(76.5%) patients, respectively (P < 0.05). Among the patients with single infarctions, the small perforating infarct(SPAI) in the stenosis and occlusion groups were 11 (11/15) and 2(2/8) patients(P = 0.039); among the patients with multiple infarctions, the perforating artery infarct(PAI) complicated with cortical infarction(pial infarct, PI) were 7(7/12) and 3(3/26) patients(P = 0.005); among the patients with multiple infarctions, PAI complicated with PI and border-zone infarct(BZI) were 1(1/12) and 16(16/ 26) patients(P = 0.004); there were 5 and 23 patients with BZI(P < 0.001). Conclusions: The sites of cerebral infarction caused by atherosclerotic stenosis and occlusion of main-stem of MCA has significant difference. It is suggested that there are different pathogenesis between them. Cerebral infarction caused by MCA stenosis may be resulted from the ostial lesion of the perforating artery and embolism. The former caused more single infarctions and the latter caused more multiple infarctions.
No preview · Article · Jun 2008 · Chinese Journal of Cerebrovascular Diseases
[Show abstract][Hide abstract]ABSTRACT: Objective: To evaluate the accuracy of dual source 64-slice CT angiography (CTA) in the diagnosis of internal carotid stenosis. Methods: Forty-one patients (82 internal carotid arteries) with cerebral ischemia of the anterior circulation were scanned with dual source 64-slice CTA, and revascularization and axial image for measuring vessel diameter were performed with multiplanar reconstruction (MPR), curved planar reformation (CPR), maximum intensity projection (MIP) and volume render (VR). The classification of stenotic degree was performed by using North American symptomatic carotid endarterectomy trial (NASCET). DSA was used as a standard of examination result to observe the sensitivity, speciality, positive predictive value and negative predictive value of CTA examination. Results: The examination results of CTA in 70 of the 82 arteries (85.4%) were in accordance with DSA. The stenosis rate diagnosed by CTA was slightly higher in 10 (12.2%) arteries as compared with the diagnostic results of DSA, and it was slightly lower in 2 (2.4%). When the stenosis exceeded 70%, the sensitivity, specificity, positive predicting value and negative predictive value of CTA were 100%, 98.4%, 95% and 100%, respectively; when the stenosis exceeded 50%, the sensitivity, specificity, positive predicting value and negative predictive value of CTA were 100%, 96.1%, 93.9% and 100%, respectively. The diagnostic results of CTA were positively correlated with those of DSA (r = 0.96, P < 0.01). Calculating the regression equation of DSA from CTA is Y(DSA) = 0.965X (CTA) - 1.305. Conclusion: CTA has very high correlation with DSA in diagnosing the degree of carotid stenosis, and can be used as a routine examination of carotid stenosis screening.
No preview · Article · Dec 2007 · Chinese Journal of Cerebrovascular Diseases