The Role And Mechanism Of E-selectin In The Pathogenesis Of Stroke A Systematic Review Of Angiotensin Receptor Blockers In Preventing Stroke

Objectives: Hypertension is one of the most common cardiovascular diseases with high incidence (18.8 %) and mortality resulting from stroke, myocardial infarction, congestive heart failure and end-stage renal disease in China. As the major complication of hypertension, stroke makes a considerable contribution to morbidity and mortality especially for young people. It constitutes a formidable burden of disability and misery for the patients and their relatives and the wider community. Many stroke survivors become dependent, and require lifelong assistance. Given the disease burden of stroke, prevention is an important public health concern to curb the stroke pandemicly. Blood pressure level is one of the most consistent and powerful predictor of stroke. Hypertension accounts for 80 % of stroke risk and 52 % of cerebral infarction attack. So blood pressure control has been conclusively shown to prevent stroke. However, blood pressure level is not the unique determinant for stroke. Here we propose other important determinants for stroke.Accumulating evidence suggests that inflammation plays important roles in the development of acute cerebrovascular disease. Inflammation has been implicated as a secondary mechanism underlying neuronal injury induced by ischemia. A variety of experimental models, including thromboembolic stroke, focal and global ischemia, have been used to evaluate contributions of inflammation to neuronal damage. Endothelial dysfunction represents an early phase of inflammation. Adhesion molecules are involved in leukocyte rolling, firm adhesion and transmigration across endothelial cells, and play an important role in inflammatory disorders. The vasculature endothelium promotes inflammation through upregulation of adhesion molecules that bind to circulating leukocytes and facilitate migration of leukocytes into the central nervous system (CNS). Once being in the CNS, leukocytes produce cytotoxic molecules that promote cell death. During this process, E-selectin is needed to play as an initiator. E-selectin belongs to the selectin family of adhesion molecules and is observed only on activated endothelium. It can serve as an activated endothelial marker. A clinical study indicated that inflammatory factors including E-selectin are involved in the development from intracranial arteriosclerosis to stroke, and serum E-selectin can serve as a predictor. It was found in another study that soluble E-selectin level is highest in patients with cerebral infarction, slight lower in patients with reversible ischemic attack, and lowest in patients with transient ischemic attack, indicating that E-selectin is related to the severity of stroke. These results suggest the promise for the therapy of stroke by using antagonists of E-selectin.As mentioned above, E-selectin is an important adhesion molecule and involved in the onset and pathologic lesion of stroke. But what are the exact mechanisms for the involvement of E-selectin in stroke? Whether E-selectin can be the target for stroke prevention and treatment? In this study, we mainly focussed on these two questions. The effect of E-selectin on stroke and the possible mechanisms involved were investigated. It might develop a new way to find the effective factors involved in the prevention and treatment of stroke. Recent results obtained in clinical trials for asthma and psoriasis show that, although very challenging, the development of E-selectin antagonists holds concrete promise for the therapy of inflammatory diseases.Methods: E-selectin levels of brain and serum were compared between spontaneously hypertensive rats (SHRs) and stroke-prone spontaneously hypertensive rats (SHR-SPs) after a normal diet or a high salt diet (4 % NaCl) was given for 1 month. To further verify the role of E-selectin on stroke, animal model of acute ischemic stroke by electric coagulation of middle cerebral artery were made in E-selectin knockout (Es-/-) mice and C57 mice. The infarct area and hemisphere areas of each section (both sides) were traced and quantified by an image analysis system. Infarct area and neurological score were compared between these two animals. The possible mechanisms of the involvement of E-selectin in stroke were studied in Es-/- mice and C57 mice. The effect of E-selectin on neutrophil infiltration was examined by detecting MPO level in brain using western blot method. To examine the effect of E-selectin on inflammation, levels of IL-6, IL-1βand TNF-αin brain were detected using ELISA method 8 h after MCA occlusion. In situ detection of apoptotic cell by the TUNEL method was performed 24 h after MCA occlusion.Results: The brain and serum E-selectin levels were higher in SHR-SPs than in SHRs (P<0.05) after salt intake, suggesting that E-selectin might be one of the key processes in the pathogenesis of stroke. The ratio of the infarct area and hemisphere areas and neurological score were significantly decreased in Es-/- mice than in C57 mice. MPO level was much lower in Es-/- mice than in C57 mice after MCA occlusion, suggesting neutrophil infiltration was significantly relieved by inhibiting E-selectin expression. IL-1βlevel was significantly higher in C57 mice than in Es-/- mice, but there was no difference in IL-6 and TNF-αlevels between these two animals. Cell apoptosis was significantly lessened in Es-/- mice than in C57 mice.Conclusions: The present study provides evidence that E-selectin is involved in the pathogenesis of stroke. Inhibiting expression of E-selectin presents protective effect on ischemic lesions. This protective effect results from the inhibition of neutrophil infiltration and the reduction of IL-1βlevel, and then relieving the cell apoptosis induced by ischemia. Objectives: Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used in patients who are at high risk of cardiovascular events. A consensus has emerged that ACEI can reduce the risk of stroke. This research of overviews of randomized trials was established to investigate the effects of ARB on the prevention of stroke in patients at high risk for cardio-cerebrovascular events.Methods: Electronic databases were searched up to December, 2008, for randomized clinical trials concerning ARB treatments in patients at high risk for cardio-cerebrovascular events. A selection criterion was established to select and evaluate the appropriate literature by comparing randomized trials of ARB with placebo, ACEI, and calcium antagonists. Data were extracted for patients'characteristics, interventions, quality of trials, and rates of stroke. The efficacy measures were the odds ratios of strokes. We did separate overviews of trials comparing ARB with placebo, with ACEI, and with calcium antagonists. The pooled effects were calculated using the random effects model by RevMan 5.0.Results: Twenty randomized clinical trials with 108286 patients were included in the analysis. The overview of placebo-controlled trials (11 trials, 44971 patients) revealed ARBs was associated with a significant reduction in the risk of stroke, with a pooled odds ratio of 0.91 (0.84 to 0.98). In the overview of trials comparing ARB with ACEI (6 trials, 36537 patients), there were no significant reduced risks of stroke with ARB (odds ratio 0.93, 0.84 to 1.03). In the overviews comparing ARB with calcium antagonists (4 trials, 22446 patients), no significant difference was found, with a pooled ratio of 1.16 (0.91 to 1.48).Conclusion: Significant benefits of ARB on the risk of stroke are demonstrated by comparing to the overviews of placebo-controlled trials. There was no evidence of differences when comparing ARB with ACEI, and with calcium antagonists. Therefore, ARB should be regarded as suitable treatments for preventing stroke in patients who are at high risk of cardiovascular events.