| 摘要: | 氧化壓力引起的心肌細胞功能失調及血管內皮產生病變是造成包括動脈硬化、高血壓及心臟衰竭等心 臟血管疾病的主要原因，而當歸是被廣泛使用的中醫處方也是能治療上述心血管老化疾病的重要候選藥品 之ㄧ。食品添加劑中常見的三級丁基過氧化氫是一短鏈的類脂質過氧化氫是常被用來誘發氧化壓力引起的 細胞衰老的模式。所以，本研究將分析當歸是否能減少三級丁基過氧化氫在離體培養的大鼠動脈內皮細胞、 心肌細胞及不同週齡的大鼠心臟及主動脈中引起的細胞毒性作用。透過本計劃的研究，可了解添加當歸萃 取物是否能藉由清除自由基及一氧化氮等、降低端粒縮短DNA 受損作用，以及其參與粒線體路徑、細胞死 亡接受器路徑或經由內質網的細胞死亡訊息傳遞以保護血管內皮及心肌細胞受到急性氧化壓力所造成的老 化及細胞凋亡作用。在未來的三年我們將完成以下研究: 第一年計劃，我們將探討當歸萃取物保護三級丁基過氧化氫誘發大白鼠動脈內皮細胞的功能失調，如 自由基生成、一氧化氮形成、細胞發炎激素基因及蛋白的表現、抗氧化酵素活性、粒線體膜電位以及細胞 凋亡相關基因的訊息傳遞。此外，我們也將探討當歸保護三級丁基過氧化氫的作用機制是否透過降低端粒 酶活性、減少端粒縮短以及改變粒線體DNA 拷貝數等作用進而減少內皮細胞功能失調。 第二年計劃，我們將探討當歸萃取物保護三級丁基過氧化氫引起大白鼠心肌細胞老化作用，如自由基 生成以及細胞凋亡相關基因的訊息傳遞。此外，我們也將探討當歸保護三級丁基過氧化氫的作用機制是否 能透過降低端粒酶活性、減少端粒縮短以及改變粒線體DNA 拷貝數等作用以減少心肌細胞老化及死亡。 第三年計劃，我們將探討當歸萃取物對抗不同週齡的老鼠受到三級丁基過氧化氫引起的心臟及主動脈 急性氧化傷害。分析其是否與抗發炎、抗氧化及防止粒線體DNA 拷貝數改變和減少端粒酶活性增加等機制 有關，進而使功能失調的心血管細胞恢復年輕活性。 完成這個研究，將有助於我們了解當歸可以對抗食品添加劑三級丁基過氧化氫引起心血管功能及結構 改變所產生的發炎反應、粒線體特性改變及細胞凋亡等作用，以提昇未來開發預防當歸萃取物為預防氧化 壓力引起的心血管老化疾病之保健食品的潛能。
Oxidative stress induced cardiac dysfunction and pathophysiological impacts in vascular endothelium is considered to be the major cause for the development of cardiovascular diseases including atherosclerosis, hypertension, and congestive heart failure. Angelica sinensis (AS), a potent candidate for the treatment of those diseases, is commonly used in Traditional Chinese Medicine. Tert-butyl hydroperoxide (t-BHP), a short-chain lipid hydroperoxide analog as food additives, has been used to the induction of oxidative stress-induced premature senescence. In this study, we plan to investigate whether AS is able to ameliorate the tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity in cultured rat aorta endothelial cells (RAECs) and primary cardiomyocytes, and in heart and aorta from different ages of rats. Through this program, we can understand the persuasive effects of AS to protect vascular endothelium and cardiomyocytes against acute oxidative damage induced-senecence and apoptosis by scavenging free radicals and nitric oxide, diminishing telomere shorten-DNA damage, and mediating mitochondrial-, cell death receptor-, or endoplasmic reticulum-dependent cell signaling system. Within three years in the future, we aim to accomplish the following goals: The first year of this program, we are going to explore the effects of AS on t-BHP induced RAEC dysfunction via ROS generation, nitric oxide formation, inflammator cytokines, antioxidant activity, mitochondrial membrane potential, and its possible roles in apoptotic cell signaling pathway. Furthermore, the protecting effects and cellular mechanisms of AS against t-BHP on endothelial dysfunction by decreasing telomerase activity, inhibiting telomere shortening and remodeling mitochondrial biogenesis will also be investigated. The second year of this program, we are going to determine the effects of AS on t-BHP induced oxidative stress and its possible roles in premature cell senescence. Furthermore, the protecting effects and mechanisms of AS against t-BHP on cardiomyocyte dysfunction via inhibiting telomerase activity, diminishing telomere shortening and modernizing mitochondrial biogenesis will be examined. The last year of this program, we are going to study the potent protective effects of AS againt t-BHP induced acute oxidative damage in heart and aorta from different ages of SD rat. Again, we also hope to understand whether AS ameliorate t-BHP-induced senescence were related to its anti-inflammation, anti-oxidation, mitochondrial biogenesis, and telomerase activity to restore damaged cardiovascular function. Results from these experiments can provide better understandings of the antagonizing effects of AS on food additives t-BHP induced cardiovascular fucntion and structure changes via inflammation, changes of mitochondrial biogenesis and apoptosis, and enable us to discover an innovative, therapeutic approach to the prevention of oxidative stress induced-premature senescence of vascular endothelium and cardiomyocytes.Oxidative stress induced cardiac dysfunction and pathophysiological impacts in vascular endothelium is considered to be the major cause for the development of cardiovascular diseases including atherosclerosis, hypertension, and congestive heart failure. Angelica sinensis (AS), a potent candidate for the treatment of those diseases, is commonly used in Traditional Chinese Medicine. Tert-butyl hydroperoxide (t-BHP), a short-chain lipid hydroperoxide analog as food additives, has been used to the induction of oxidative stress-induced premature senescence. In this study, we plan to investigate whether AS is able to ameliorate the tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity in cultured rat aorta endothelial cells (RAECs) and primary cardiomyocytes, and in heart and aorta from different ages of rats. Through this program, we can understand the persuasive effects of AS to protect vascular endothelium and cardiomyocytes against acute oxidative damage induced-senecence and apoptosis by scavenging free radicals and nitric oxide, diminishing telomere shorten-DNA damage, and mediating mitochondrial-, cell death receptor-, or endoplasmic reticulum-dependent cell signaling system. Within three years in the future, we aim to accomplish the following goals: The first year of this program, we are going to explore the effects of AS on t-BHP induced RAEC dysfunction via ROS generation, nitric oxide formation, inflammator cytokines, antioxidant activity, mitochondrial membrane potential, and its possible roles in apoptotic cell signaling pathway. Furthermore, the protecting effects and cellular mechanisms of AS against t-BHP on endothelial dysfunction by decreasing telomerase activity, inhibiting telomere shortening and remodeling mitochondrial biogenesis will also be investigated. The second year of this program, we are going to determine the effects of AS on t-BHP induced oxidative stress and its possible roles in premature cell senescence. Furthermore, the protecting effects and mechanisms of AS against t-BHP on cardiomyocyte dysfunction via inhibiting telomerase activity, diminishing telomere shortening and modernizing mitochondrial biogenesis will be examined. The last year of this program, we are going to study the potent protective effects of AS againt t-BHP induced acute oxidative damage in heart and aorta from different ages of SD rat. Again, we also hope to understand whether AS ameliorate t-BHP-induced senescence were related to its anti-inflammation, anti-oxidation, mitochondrial biogenesis, and telomerase activity to restore damaged cardiovascular function. Results from these experiments can provide better understandings of the antagonizing effects of AS on food additives t-BHP induced cardiovascular fucntion and structure changes via inflammation, changes of mitochondrial biogenesis and apoptosis, and enable us to discover an innovative, therapeutic approach to the prevention of oxidative stress induced-premature senescence of vascular endothelium and cardiomyocytes. |
