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1、1 今日氧化应激OXIDATIVE STRESS TODAY History of Discovery Regulatory role of mitochondria inoxidative stress and atherosclerosis Oxidized Low-Density Lipoprotein and Atherosclerosis 发现的历史 : oxLDL 与动脉粥样硬化的关系Dannile Steinberg, et al. University of California, San Diego, America Arterioscler Thromb Vasc Biol
2、. 2010; 30: 2311-2316目前，在 PubMed 上通过“ oxidized LDL ”可检索到 5877篇文献，通过“ oxidized LDL 和atherosclerosis ” 可检索到 2639篇文献。Chance and serendipity play major roles in the history of science. Too often, though, their contributions do not show up in formal publications. We all tend to shape history according to
3、 the styles of the times and according to our own biases. Acknowledged or unacknowledged, there is a tendency to want the scientific “story ” to be neat and more or less linear. The genesis of the oxidized low-density lipoprotein (oxLDL) hypothesis owed a great deal to happenstance, but that may not
4、 be readily apparent from the formal articles. We take this opportunity to tell the whole story, at least as we remember it. Several apparently unrelated events occurring at about the same time in Oslo, Norway; in Cleveland, Ohio; in La Jolla, California; in New York, New York; and in Dallas, Texas
5、converged to lay the groundwork for the hypothesis that oxidative modification of LDL might be important in atherogenesis. Later developments regarding the relationship between oxLDL and the immune system in atherogenesis, again, were often smiled on by chance and serendipity. ” Chance again played
6、a key role in pointing us to probucol as an ideal agent for testing our hypothesis in animal models of atherosclerosis. One day Sampath Parthasarathy was given some labeled LDL by Naruscewicz and got almost no in vitro modification! Yes, he had obtained LDL that had been harvested from a probucoltre
7、ated rabbit. We quickly were able to show that probucol was indeed a potent inhibitor of LDL oxidation. ”机遇和运气在科学发展史上扮演着重要角色，然而，正式出版物多半不会提及机遇和运气。我们都倾向根据时代风格和自我偏见去塑造历史。无论承认与否， 我们始终倾向于科学 “ 故事”应该秩序井然，并且或多或少呈现线性关系。oxLDL （氧化低密度脂蛋白 )）的理论在很大程度上源于偶然发现，然而正式文献不会乐于这样报道。我们借此机会告诉大家整个故事，至少我们还记得它。在挪威奥斯陆、俄亥俄州克利夫兰、加
8、利福尼亚州拉霍亚、纽约市和得克萨斯州达拉斯，几乎在同一时间段， 发生了几个看似无关的事件， 这些事件共同奠定了oxLDL理论的基础，该理论认为LDL 的氧化修饰可能与动脉粥样硬化形成密切相关。之后，我们再次幸运地发现了动脉粥样硬化中oxLDL 与免疫系统的关系。“ 发现普罗布考是抗动物动脉粥样硬化的理想药物时，机会再次起到非常重要的作用。一天， Sampath Parthasarathy 教授收到 Naruscewicz 教授给的一些标记性LDL，且几乎全部在体外未经氧化修饰！是的，这些LDL 来自接受普罗布考治疗的兔子。不久，我们就发现普罗布考是抑制LDL 氧化修饰的有效药物。”Regula
9、tory Role of Mitochondria Inoxidative Stress and Atherosclerosis 线粒体在氧化应激和动脉粥样硬化形成中的调节作用Jui-Chih Chang, et al Changhua Christian Hospital, Changhua Taiwan, China World J Cardiol 2010; 2(6): 150-159 本文回顾了线粒体生物合成介导的分子机制，动脉粥样硬化危险因子通过该通路可导致线粒体功能异常及随后的血管损伤，有助于我们理解线粒体对抗氧化应激的机制；并对 AST/CVD进展过程中线粒体的生理作用提出不同认
10、识。Mitochondrial physiology and biogenesis play a crucial role in the initiation and progression of cardiovascular disease following oxidative stress-induced damage such as atherosclerosis (AST). Dysfunctional mitochondria caused by an increase in mitochondrial reactive oxygen species (ROS) productio
11、n, accumulation of mitochondrial DNA damage, and respiratory chain deficiency induces death of endothelial/smooth muscle cells and favors plaque formation/rupture via the regulation of mitochondrial biogenesis-related genes such as peroxisome proliferator-activated receptor coactivator(PGC-1), altho
12、ugh more detailed mechanisms still need further study. Based on the effect of healthy mitochondria produced by mitochondrial biogenesis on decreasing 3 ROS-mediated cell death and the recent finding that the regulation of PGC-1 involves mitochondrial fusion-related protein (mitofusin), we thus infer
13、 the regulatory role of mitochondrial fusion/fission balance in AST pathophysiology. In this review, the first section discusses the possible association between AST-inducing factors and the molecular regulatory mechanisms of mitochondrial biogenesis and dynamics, and explains the role of mitochondr
14、ia-dependent regulation in cell apoptosis during AST development. Furthermore, nitric oxide has the Janus-faced effect by protecting vascular damage caused by AST while being a reactive nitrogen species (RNS) which act together with ROS to damage cells. Therefore, in the second section we discuss mi
15、tochondrial ATP-sensitive K+channels, which regulate mitochondrial ion transport to maintain mitochondrial physiology, involved in the regulation of ROS/RNS production and their influence on AST/cardiovascular diseases (CVD). Through this review, we can further appreciate the multi-regulatory functi
16、ons of the mitochondria involved in AST development. The understanding of these related mechanisms will benefit drug development in treating AST/CVD through targeted biofunctions of mitochondria. 在氧化应激引起的损伤中，线粒体的生理机能和生物合成起到了至关重要的作用，如动脉粥样硬化形成（ AST ）及随后的心血管疾病发生和发展过程。线粒体内活性氧簇（ROS）生成增多，线粒体 DNA 不断损伤及呼吸链功能失调均可使其功能失调，通过调节线粒体生物合成相关基因（如过氧化物酶体增殖活化受体共激活因子 -1，PGC-1 ） ，诱导内皮细胞 /平滑肌细胞死亡并促进斑块形成和破裂，但更详细的机制仍需进一步研究。健康线粒体能够降低ROS 介导的细胞死亡，而最近研究发现：PGC-1 的调控涉及到线粒体聚合相关蛋白（线粒体融合蛋白），因此我们推断，线粒体融合/分裂平衡的调节在AST 的病理生
