2010-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/671653摘要：低溫治療是近來發展具有保護效果的治療，心跳停止患者經急救成功後施予低溫治療(therapeutic hypothermia)，確可改善存活預後並減少缺血再灌流傷害。低溫治療之心臟保護作用，雖初步了解與保存粒線體功能完整性有關，然其機轉卻仍未明瞭。Peroxisome proliferator activated receptor-γ coactivator-1α(PGC-1α)是近來發現調控粒線體功能之重要因子，經由其作用可增加受損細胞粒線體生合成，以維持細胞存活，其所透過的路徑如MAPK 等也與細胞存活有關。低溫的環境下，PGC-1α會被活化並透過粒線體產生能量以維持體溫，然而其於低溫治療之心臟保護作用中的角色則未明。本研究之目的為應用模擬缺血再灌流之心肌細胞培養及動物急救模式，來探討低溫治療產生心肌保護之機轉及PGC-1α相關路徑之角色。初步研究顯示低溫處理產生之心肌保護作用，與減低鈣離子過度負荷及保存粒線體完整性有關，同時也能穩定PGC-1α的表現及維持細胞內ATP的量。初步動物實驗的結果也顯示低溫治療可穩定急救後之心臟功能，並活化相關存活路徑。在本研究計畫中，吾人將確認低溫治療對粒線體功能的影響，並透過調控PGC-1α，來探討其於低溫治療中的角色及與相關上、下游路徑之作用，並以動物模式來探討並確認細胞實驗中之保護作用及PGC-1α相關機轉於生物體內之效果，以做為潛在臨床應用之基礎。<br> Abstract: The application of hypothermia treatment is a great progression to improve theprognosis and the survival in the post-resuscitated cardiac arrest patients recently. Theimpact of therapeutic hypothermia on the heart is the effect of cardioprotection. Thehypothermia treatment limits the post-cardiac arrest syndrome, which is featured by thewhole body ischemia-reperfusion injury and myocardial dysfunction. The post-cardiac arrestsyndrome is the most important direct cause of death after cardiac arrest and cardiopulmonaryresuscitation. The mechanisms proposed for the hypothermia treatment includedecreasing the ischemia-reperfusion related myocardial injuries by strengthening theanti-apoptotic pathways, preservation of mitochondria integrity and functions. However,they are preliminary and not comprehensive. Peroxisome proliferator activated receptor-γcoactivator-1α (PGC-1α) is one of the key factors regulating the mitochondria mass andfunctions. Up-regulating PGC-1α can maintain the mitochondria biogenesis for the damagedcardiomyocytes and survive the cells through activation of the downstream transcriptionfactors for stabilizing mitochondria functions. It also interact with the pro-survival pathwayssuch as MAPK pathways. Expression of PGC-1α is increased under cold environments togenerate heat through increasing the energy generation by mitochondria. However, its rolesin the cardioprotection effects in hypothermia treatment remain unclear.The goals of the project are to investigate the mechanisms and roles of PGC-1α incardioprotective effects by therapeutic hypothermia using the in vitro cardiomyocyte culturemodel mimicking ischemia-reperfusion and in vivo cardiac arrest and resuscitation animalmodels we have established respectively. The cardiomyocyte survival is better and apoptosisis less with the hypothermia treatment after hypoxia-reoxygenation injuries in ourpreliminary cell culture study results. The cardioprotection effect is related to the decreasingof intracellular and mitochondria calcium overloading as well as preservation mitochondrialmembrane potential and permeability transition pore integrities. Hypothermia treatment alsomaintains the expression level of PGC-1α and ATP amount without decreasing after cellsinjured. In the post- resuscitation animal studies, the hypothermia treatment improves thesurvival rate and cardiac performance. The pro-survival kinase (ERK) is found moreactivated in the hypothermia treatment group. In this project, we will investigate themechanisms of hypothermia-induced cardioprotective effects focusing on the mitochondriafunctions and elucidate the roles of PGC-1α related pathways. The effects of hypothermia onthe preservation of mitochondria integrity and biogenesis will be stressed. Also we willstudy the significance of PGC-1α in hypothermia related cell protection effects by up anddown regulating the expression level of PGC-1α in the cardiomyocytes. After elucidating thehypothermia treatment protection pathways networks and roles of PGC-1α, we will use thecardiac arrest and resuscitation animal models for in vivo study to investigate the proposedmechanisms from the in vitro studies. Since there may be a gap between the environments ofcardiomyocytes in the in vitro and in vivo studies, the animal studies will focus ondemonstration and confirmation of the cardioprotective mechanisms and significance ofPGC-1α in the hypothermia treatment after cardiac arrest and resuscitation. The results canbe a basis for the clinical studies and utility in the future.