二型糖尿病和肥胖症業已成為威脅人類健康的世界性難題。二型糖尿病和肥胖症與心血管疾病的發生發展緊密相關，這是患者致死致殘的最常見原因。因此，揭示糖尿病和肥胖導致心血管疾病的細胞機制，發展更有效而低副作用的治療策略是目前極需研究的課題。本論文主要對以下幾個方面進行了研究探討，第一，在糖尿病和肥胖小鼠中，內質網應激和氧化應激在其內皮功能障礙中的病理學作用；第二，內質網應激能否成為干預靶點；第三，運動鍛鍊改善內皮功能和降低血管炎症，是如何通過限制內質網應激及調節其他糖尿病和肥胖相關的細胞機制來實現的。 / 論文的第一部份揭示了內質網應激及氧化應激在糖尿病內皮功能障礙中所起的關鍵作用。離體組織培養實驗結果顯示，內質網應激誘導劑衣霉素可以顯著地損傷乙酰膽鹼誘導的血管內皮依賴性舒張（EDR），並增加活性氧自由基（ROS）的產量。用內質網應激緩和劑四苯基乙酸（4-PBA）和牛磺酸共軛熊脫氧膽酸（TUDCA）處理血管，可以修復衣霉素和其他風險因子，如高糖，骨形成蛋白4（BMP4）等損傷的血管舒張。類似，ROS清除劑可以減輕衣霉素誘導的EDR損傷。此外，衣霉素可以抑制元代培養的小鼠主動脈內皮細胞的一氧化氮（NO）產量，而這種抑制效果可以被4-PBA和TUDCA逆轉。對db/db糖尿病小鼠用PBA和TUDCA進行慢性口服治療後，內皮功能得到明顯改善，上調的內質網應激得以恢復正常，同時一氧化氮合酶（eNOS）的活性顯著提高，這些結果支持了內質網應激在糖尿病中的病理學作用，提供了內質網應激緩和劑治療糖尿病內皮障礙的的可能性。 / 論文的第二部份研究了過氧化物酶体增殖物活化受體δ(PPARδ) 在抗糖尿病藥物二甲雙胍誘導的腺苷單磷酸活化蛋白激酶（AMPK）激活對血管保護中的作用，及其與內質網應激的聯繫。實驗結果顯示，在食誘導肥胖（DIO）的PPARδ野生型小鼠中，慢性口服二甲雙胍治療可以改善EDR，抑制內質網應激的標誌性蛋白表達和ROS的過高產量，並提高主動脈eNOS的磷酸化水平。這些血管保護效應在PPARδ敲除的DIO小鼠中消失。體內實驗的結果在體外得以證實，二甲雙胍改善EDRs，提高PPARδ的表達和eNOS的磷酸化，抑制小鼠主動脈內質網應激標誌物的表達，並提高了小鼠內皮細胞的NO產量。所有這些效應都可以被PPARδ的抑製劑GSK0660阻斷。這些結果闡明了在AMPK激活劑作用條件下，PPARδ在降低內質網應激，抑制氧化應激和提高NO產量中的顯著作用。 / 生活方式的優化，例如日常的體育鍛鍊，一直以來就被視為改善血管和代謝的重要方式，但這其中的機制並不完全清楚。因此，論文的第三部份主要探索了運動對血管的改善作用。實驗結果顯示，對db/db糖尿病小鼠進行跑步訓練后，導管動脈和阻滯動脈的EDR得到明顯改善，過高內質網應激，炎性反應和氧化應激，以及內皮細胞中被抑制的AMPK和eNOS都會恢復正常。此外，運動對血管功能的保護作用在DIO的PPARδ 野生型小鼠中可以實現。但是，在DIO的PPARδ敲除小鼠中，增加的內質網應激及其氧化應激卻不因運動鍛鍊而降低。這些結果揭示了糖尿病和肥胖中，PPARδ作為保護血管功能的運動誘導信號的關鍵效應器。 / 總而言之，論文的研究提供了一系列新穎的機制和證據，支持了AMPK依賴的PPARδ激活和內質網應激緩解作為潛在的治療策略用於抵抗糖尿病血管病變。這些新發現同樣也為二甲雙胍在臨床上的使用提供了有益的信息，同時為代謝綜合徵病人通過增強運動機能來有效地保護血管功能提供了有效參考。 / Type 2 diabetes mellitus and obesity increasingly represent a global health problem and are associated with the development and progression of cardiovascular disease which is one of leading causes of mortality and disability worldwide. Hence, there is an urgent need to delineate clearer cellular mechanisms of cardiovascular outcomes in diabetes and obesity, and to develop more effective therapeutic strategies with fewer side effects. The present study aimed at examining (1) the pathological role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) over-production in the induction of endothelial dysfunction in diabetic and obese mice, (2) whether ER stress is a therapeutic target, and (3) whether physical exercise improves endothelial function and reduces vascular inflammation through limiting ER stress and other regulatory cellular mechanisms involved in diabetes and obesity. / The first set of experiments show that ER stress and associated oxidative stress serves as a key contributor to endothelial dysfunction in diabetes. The results from ex vivo tissue culture with aortas show that ER stress inducer tunicamycin markedly impairs acetylcholine-induced endothelium-dependent relaxations (EDR) in company with elevated ROS production. Treatment with ER stress alleviators 4-phenyl butyric acid (PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA) restore the impaired relaxations in arteries treated with tunicamycin and other risk factors, high glucose and bone morphogenic protein 4 (BMP4). Likewise, ROS scavengers attenuate tunicamycin-induced impairment of EDR. In addition, tunicamycin reduces nitric oxide (NO) production in primary culture mouse aortic endothelial cells; and its inhibitory effect on NO bioavailability was reversed by co-treatment with PBA and TUDCA. Chronic daily oral administration of PBA and TUDCA rescues endothelial function, normalizes the upregulation of ER stress and oxidative stress, and enhances endothelial NO synthase (eNOS) activity in the aortas from db/db mice, thus supporting a pathological role of ER stress as well as the therapeutic potential of ER stress alleviators in preserving endothelial function with diabetes. / The second series of experiments examined the role of peroxisome proliferator-activated receptor delta (PPARδ) in vascular benefits of activation of AMP-activated protein kinase (AMPK) induced by the anti-diabetic drug metformin in connection with ER stress. Chronic oral metformin treatment improves EDR, inhibits the expression of ER stress markers and ROS over-production, and increases phosphorylation of eNOS in aortas from diet-induced obese (DIO) PPARδ wild-type (WT) mice. These beneficial effects were absent in DIO PPARδ knockout (KO) mice. The benefits of chronic metformin administration are supported by the in vitro data showing that metformin ameliorates EDR, increases PPARδ expression and eNOS phorsphorylation, and suppresses the expression of ER stress markers in mouse aortas; and enhances NO production in mouse endothelial cells. All these effects were blocked by PPARδ antagonist GSK0660. The present results support a significant role of PPARδ in contributing to the reduced ER stress and oxidative stress, and to the increased NO production upon stimulation with AMPK activator. / Lifestyle modification such as regular physical exercise has long been appreciated for its vascular and metabolic benefits though the underlying mechanisms which are not fully understood. The third group of experiments explored the vascular benefits of exercise. Physical running exercise improves EDR in conduit and resistance arteries from db/db mice by normalizing the increased expression or levels of ER stress, inflammation, and oxidative stress, as well as by restoring the diminished activities of AMPK and eNOS in endothelial cells. Vascular benefits were also observed in DIO PPARδ WT mice. However, increased ER stress and associated oxidative stress cannot be reduced by exercise in DIO PPARδ KO mice. These results elucidate that PPARδ serves as a key mediator of exercise-induced signaling that mediate the vasoprotective effect of exercise in diabetes and obesity. / To summarize, the present investigation has provided several lines of novel mechanistic evidence in support for the positive role of AMPK-dependent PPARδ activation and ER stress alleviation as potentially therapeutic target to combat against diabetic vasculopathy. The new findings of the present study also provide useful information in support of the clinical utilization of metformin and recommendation of increased physical activity as another effective measure to preserve vascular function in patients with metabolic syndrome. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Cheang, Wai San. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 131-152). / Abstracts also in Chinese.

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