抑制血栓素及血栓素受體訊號減輕血管內皮素-1及缺血再灌流所引起的心臟損傷
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2017
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心血管疾病包括冠心病、心絞痛、急性心肌梗塞等等，為世界死因之首。根據台灣衛生福利部的統計，我國心血管疾病為第二大死因，每十萬人就有88.1人於心血管疾病，僅次於惡性腫瘤的199.6人。心肌缺血會使心肌細胞發生強烈的發炎反應且再灌流後會使冠狀動脈釋放出大量活性氧物質，而活性氧物質又促進血栓的形成，影響到血栓素合成酶(Thromboxane A2 synthase, TXAS)-血栓素 (Thromboxane A2, TXA2)-血栓素受體 (Thromboxane prostanoid receptor, TP receptor)訊息傳遞路徑，包括增加了血栓素合成酶(Thromboxane A2 synthase, TXAS)的表達和血栓素受體(Thromboxane prostanoid receptor, TP receptor)的活性，最終增加了血管內皮素(Endothelin-1, ET-1)釋放造成更加嚴重的傷害。
本篇研究即是要探討抑制掉TXAS-TXA2-TP訊息傳遞路徑後，ET-1所喚起的傷害和在心肌缺血再灌流的傷害上扮演著什麼樣的角色。我們使用三種不同基因型的老鼠，TXAS+/+TP+/+、TXAS-/-TP+/+及TXAS-/-TP-/-小鼠並將實驗分為以下幾組。
1. 所有的小鼠將被隨機靜脈注射生理實驗水、U46619 (TXA2 agonist, 2 mg/kg)和ET-1(0.001-0.2 µg/kg)測量其心臟微循環，共四組(各組N=6)。
2. 所有的小鼠將被隨機執行血管環模型實驗(wire myography)，測量其血管對藥物(norepinephrine, acetylcholine, U46619, ET-1 )的收縮或舒張反應，共四組(各組N=6)。
3. 所有的小鼠將被隨機執行心肌缺血再灌流模型(myocardial ischemia/reperfusion model)手術，共四組(各組N=6)。
並搭配組織免疫染色、血漿心肌旋轉蛋白(Troponin I)含量測定來看探討其細胞凋亡、細胞自噬、發炎性細胞凋亡和發炎之分生機轉及心肌梗塞之嚴重程度。
我們的研究結果指出抑制TXAS-TXA2-TP訊息傳遞路徑，可以有效的減少心肌缺血再灌流所引起的細胞凋亡、發炎性細胞凋亡和氧化壓力，對小鼠具有較佳之心臟保護效果。
Cardiovascular disease has become one of the most harmful human diseases with highest morbidity in the world, especially coronary heart disease and myocardial infarction. According to Ministry of Health and Welfare, the cardiovascular disease is the second cause of death and accounts for 0.881‰ death per year in Taiwan, second only to cancer. Myocardial ischemia/reperfusion (I/R) induces the release of oxidants in coronary arteries. Following the production, the oxidants may activate platelets and consequently induce thrombus formation. It is well known that thromboxane A2 synthase (TXAS) —thromboxane A2 (TXA2)—thromboxane prostanoid receptor (TP)— would activate TP, and increasing release of endothelin-1 (ET-1) to bring about more serious injury. In order to explore the role of TXAS-TXA2-TP pathway in endothelin-1 (ET-1) activation during I/R injury, we utilized mouse with gene depletion in TXAS (TXAS–/–) and both TXAS and TP (TXAS–/–TP–/–) mice. All mice were randomly subjected to intravenous normal saline, endothelin-1 (0.001-0.2 µg/kg body weight), U46619 (TXA2 agonist, 2 mg/kg body weight). Using Wire myograph model to determine the vascular reactivity of rat mesentery arteries, we investigated the possible signaling pathway between ET-1 and TXAS-TXA2-TP. In myocardial I/R model, the cardiac injuries were evaluated by microcirculation, electrocardiogram and plasma troponin I. We explored the mechanisms including apoptosis, pyroptosis and inflammation via level of plasma troponin I and immunohistochemistry stain in these animals. Our results indicate that the inhibition of TXAS-TXA2-TP pathway provides cardiac protection against myocardial I/R injury.
Cardiovascular disease has become one of the most harmful human diseases with highest morbidity in the world, especially coronary heart disease and myocardial infarction. According to Ministry of Health and Welfare, the cardiovascular disease is the second cause of death and accounts for 0.881‰ death per year in Taiwan, second only to cancer. Myocardial ischemia/reperfusion (I/R) induces the release of oxidants in coronary arteries. Following the production, the oxidants may activate platelets and consequently induce thrombus formation. It is well known that thromboxane A2 synthase (TXAS) —thromboxane A2 (TXA2)—thromboxane prostanoid receptor (TP)— would activate TP, and increasing release of endothelin-1 (ET-1) to bring about more serious injury. In order to explore the role of TXAS-TXA2-TP pathway in endothelin-1 (ET-1) activation during I/R injury, we utilized mouse with gene depletion in TXAS (TXAS–/–) and both TXAS and TP (TXAS–/–TP–/–) mice. All mice were randomly subjected to intravenous normal saline, endothelin-1 (0.001-0.2 µg/kg body weight), U46619 (TXA2 agonist, 2 mg/kg body weight). Using Wire myograph model to determine the vascular reactivity of rat mesentery arteries, we investigated the possible signaling pathway between ET-1 and TXAS-TXA2-TP. In myocardial I/R model, the cardiac injuries were evaluated by microcirculation, electrocardiogram and plasma troponin I. We explored the mechanisms including apoptosis, pyroptosis and inflammation via level of plasma troponin I and immunohistochemistry stain in these animals. Our results indicate that the inhibition of TXAS-TXA2-TP pathway provides cardiac protection against myocardial I/R injury.
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缺血再灌流傷害, 血栓素及血栓素受體訊息, 血管內皮素-1, 急性心肌梗塞, Ischemia and Reperfusion Injury, TXAS-TXA2-TP Signaling, Acute Myocardial Infarction, Endothelin-1