| Stroke, also called cerebrovascular accident, constitutes a significant human health hazard because of its high incidence, morbidity and mortality. In the past ten years, clinical trials aiming to figure out suitable neuroprotectants against the debilitating effects of stroke have met with no success. Identifying novel neuroprotectants which can reverse the effects against stroke is becoming a challenge to both clinicians and scientists. Ischemic stroke is the most common stroke category which accounted to70%of stroke. The lingering effects of ischemic stroke are very serious, resulting in patient death, and most of survivors suffer nerve function disorder. The consequence of stroke is often enhanced by risk factors such as diabetes, which increases the incidence of stroke in the ischemic stroke by4to12folds particularly. Acute hyperglycemia and diabetes could aggravate brain damage, because the transient focal or forebrain ischemia by both glutamate excitotoxicity and increased reactive oxygen species (ROS) generation. Additionally, the excessive glucose supply is suggested to upregulate the glucose transporters levels and△Ψm, which might be detrimental to the brain cells. The results of these above risk factors are the extension of core region or conversion of penumbra into the core in a short time. The reasons that diabetic patients may associate with ischemic stroke including susceptibility genes, hypercoagulable state, high blood sugar, lipid metabolism disorders, hormone regulation disorders.So finding the related genes in ischemic stroke can predict the happening of ischemic stroke and decrease the damage of nerve function to become the focus question of research in ischemic stroke.Recent reports on the uncoupling protein-2(UCP-2) appears it has nerve protection on ischemic stroke. The functional structure of UCP-2is a homodimer composed of309amino-acid residues. It is present on chromosomes11and7in the human and mouse, respectively. The primary function of UCPs in the mitochondria is translocation of protons, which are pumped out against concentration gradient during the flow of electrons through respiratory chain complexes Ⅰ-Ⅳ. The proton electrochemical gradient, the△Ψm, established by these protons is used to synthesize adenosine triphosphate (ATP) by FOF1-ATPase (complex V). However, the consumption of oxygen during electron transport chain (ETC) may not be completely used to concomitant ATP generation because of proton leak through UCPs, and the resultant energy of the△Ψm is dissipated as heat. The protons may be directly transported by UCPs or indirectly through a process called fatty acid cycling across the IMM. The exact mechanism of proton transport although is not clear, however, both processes suggested may uncouple the oxidation from ATP synthesis. When ischemic stroke happened, uncoupling protein-2can decrease the mitochondrial membrane potential, regulate the calcium overload, decrease the ROS production. By that means, UCP-2protects the nerve cells. Now more and more investigations confirm UCP-2-866G>A SNP is a functional polymorphism. A series of clinical studies showed associations of this polymorphism with several phenotypes related to obesity, diabetes, insulin sensitivity, insulin secretion, and dyslipidemia. But is this SNP related in ischemic stroke and is the genetic predisposition independent from other susceptible factor? These questions now have no answer. Therefore, we focused on investigation of those questions.In the first chapter, a total of844patients were selected.404cases with cerebral thrombosis (T2DM+IS),440cases without ischemic stroke (T2DM) in4-years follow up, UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency. We found IS incidence, recurrence and death rate, the assay suggested that XA(AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.In the second and third chapter, we based on the results and continued to follow-up the patients with IS recurrence, discussing the relationship between prognosis and UCP-2gene promoter-866G>A gene type and the relevance of possible mechanism with multiple logistic regression model calculate each different genotype. We found that the patients carrying A alleles had no different recurrent rate of IS than carrying GG wild type, but carrying A alleles the patients had lower clopidogrel reactive than GG wild type of patients, the exact mechanism was still being discussed further.In conclusion, the present study first found that UCP-2gene-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women. This effect was independent of effects of other risk factors, such as age, arterial hypertension and obesity. Later, we found that during the four years follow-up, UCP-2gene mutations and the stroke of the recurrence were not obviously related, but, carrying A alleles of the patients had lower clopidogrel reactive than GG wild type of patients, the results were significantly different. This research showed that UCP-2gene promoter area-866G>A mutation had relationship with Chinese type two diabetes stroke occurrence and development. This research was good for stroke clinical and forecast. Part Ⅰ Association between mitochondrial uncoupling protein2gene-866G>A polymorphism and diabetic patients with ischemic strokeObjective:To investigate the association of uncoupling protein2(UCP-2) gene-866G>A polymorphism on diabetic patients with cerebral thrombosis.Methods:A total of844patients were selected404cases with cerebral thrombosis(T2DM+IS),440cases without ischemic stroke(T2DM), UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency.Results:The assay suggested that XA (AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.Conclusion:UCP-2-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women.Part Ⅱ Effects of uncoupling protein2-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic strokeObjective:The purpose of this study was to assess the effects of-866G>A polymorphism of mitochondrial uncoupling protein2(UCP-2) on prognosis in patients with type2diabetic companied by ischemic stroke.Methods:A total of405Chinese patients with T2DM and stroke were assessed in a4-year follow-up case-control study. The primary end point was a composite of stroke and TIA (transient ischemic attack), the secondary end point was death. The-866G>A polymorphism in UCP-2was genotyped by TaqMan MGB probe method.Results:The-866G>A SNP in UCP-2was not significantly associated with recurrence of diabetic ischemic stroke (P=0.57).Conclusion:There was no relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study. Part Ⅲ The mechanism of-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic strokeObjective:The purpose of this study was to assess the mechanism of-866G>A polymorphism on prognosis in ischemic stroke in Chinese type2diabetic patients.Methods:405patients enrolled in part II studies were measured in response to antiplatelet therapy with the Platelet Function Analyzer-100by means of collagen/adenosine diphosphate (CADP) and collagen/epinephrine (CEPI) cartridges.Results:For A allel carrying patients in comparison with GG genotype a significant trend toward non-full response to antiplatelet therapy in the CADP and CEPI test was observed (P<0.0001).Conclusion:The A allele was associated with increased risk of clopidogrel resistance.In summary, our present study has the following new concerns:1. The A allele of the-866G>A variant of UCP-2was associated with increased risk of IS In a4-year prospective study, we first found the A allele was associated with increased risk of IS in Chinese diabetic women with type2diabetes. This association was independent of other common IS risk factors.2. The A allele was associated with increased risk of clopidogrel resistance There were no exactly relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study. But the A allele was associated with increased risk of clopidogrel resistance. |
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