研究发现动脉斑块比其它更致命的原因

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研究发现动脉斑块比其它更致命的原因

美国一项新的研究已发现占小比例的动脉斑块致命并引起心脏病发作或中风的原因，以及大多数其它动脉斑块是良性的、无明显危害的原因。

该研究是位于纽约的哥伦比亚大学医学中心和纽约大学医学中心的研究者们的工作内容，于5月6日在细胞代谢学杂志上发表。

研究者们说很多人误以为动脉斑块不可避免会导致心脏病发作或中风，他们的研究发现少数斑块是真正值得去担心的原因。

他们也发现了一种负责使良性斑块转变为危险斑块的重要蛋白质。

研究者们说：然而绝大多数粥样硬化病变是无危害性的，只占2％最终会引起一个急性的常常是致命的导致心脏病发作或中风的血凝块。

Ira Tabas博士是哥伦比亚大学医学部的Richard中风杂志的教授和研究会的副主席及医学、解剖学、细胞生物学教授，他说：如何区分斑块是危险的和良性的是一个花费很高的问题。

斑块或粥样硬化病变是指形成动脉壁内层的脂肪炎性沉着物。Tabas说，这些斑块也会使白细胞如巨噬细胞聚集，而粥样硬化病变会沿着血管壁形成不同的斑块。他补充道：使它具有危险性的不是沉着物的大小而是因为沉着物位于表面下。

他形象的将它比喻成火山里的岩浆或熔岩：当动脉斑块是由死亡细胞组成的情况时，斑块中心能发出类似的隆隆声，一旦斑块破裂就会形成一个血管内腔或动脉内随血流而流动的血凝块。

他们的发现支持这样的观点，即所谓的内质网（ER）应激性与机体自然处理的方式是一致的，该方式是破裂发生的一个原因。

细胞内质网有两个作用：它产生、储存和运输新蛋白质；它控制着细胞内钙的储存和释放。

当细胞不能正常工作时，它就会突发产生一种蛋白反应，该反应可激发那些处于显著紧张状态的细胞自杀。细胞自杀现象的激发器是内质网内一种随时可激活的应激效应器，我们称之为CHOP。

Tabas说，大量细胞在不这么做的时候就会死亡，内质网正常工作时可以通过杀死任何地方的细胞来保护整个机体，但是越来越多的科学家们开始认识到内质网应激性和机体的过度增生反应是潜在的神经变性疾病、老龄化和糖尿病的公共特性。

Tabas说，然而早期的研究已经揭露了内质网应激性和易损的斑块之间的一个联系，这是一个最先表明两者之间清晰原因的联系。

Tabas说，这就是限制血液流动和能引起心脏病发作、中风或心脏猝死的突发血液凝固过程。他解释当今世界上绝大多数的人在达到20岁时都会有动脉粥样硬化，对将来提出的挑战是阻止年青人的这种病变从有害性转变成危险性，或延缓危险性斑块使它们在我们这个年龄不至于破裂。

Tabas说具体怎么去做还不是很清楚。斑块从良性变成恶性肯定有很多原因，但是其中一个肯定是和斑块中的死亡细胞有关的，后者也被研究者们称为坏死核心。

Tabas说，这些死亡细胞会释放一些物质，这些物质可削弱覆病变周围的细胞黏附蛋白从而激发出产生血凝块的信息。

研究中，Tabas和同事们饲养了两组小鼠，给予10周的高脂肪和高胆固醇饮食以建立动脉粥样硬化模型。一组小鼠去除了CHOP基因，而另一组保留该基因。无CHOP基因的小鼠比有CHOP基因的小鼠产生了更小的斑块。但是更重要的是，该研究也表明无CHOP基因的小鼠有低出50％的细胞死亡和斑块坏死比率。

他们记录道，对另一种群的动脉粥样硬化小鼠的重复性试验基本上得到了同一结果。

尽管以前的研究已经指出过前面讲到的内质网应激性和开放蛋白反应，但是Tabas说他们的研究结果仍然令人感到惊奇，特别是效应的大小。

他说：我们能孤立一个通过如此深奥的斑块效应来编码蛋白的基因这样的事实是一个很大的惊奇。

感到惊奇是因为他们正期望这只是该工作很多步骤中的一个，包括一些可用来补偿CHOP基因丢失的东西。

Tabas说，在小鼠实验中发现这种效应能应用到人类以获得真正的临床益处。

这些发现给出了一种可能性，即针对CHOP基因的靶向药物能静息内质网细胞的应激性，这是治疗美国“第一杀手”心脏病的有效方法。

抗胆固醇药能减少沉积在动脉内的斑块数量，但是它们并不对每个人都这样，包括人生早期出现沉着物，如我们10多岁时脂肪纹在动脉里的出现，20多岁时斑块的出现。

Tabas说，预防细胞死亡的一种疗法可减少易损斑块的数量，并预防70％的未服用降胆固醇药人群的心脏病发作和中风。

然而，基于该发现的有效治疗手段得到普遍采纳可能需要一定的时间，研究者们说，但是通过促使斑块里的其它细胞捕获和清除爆发前的死亡细胞的方法来绕开死亡细胞的问题仍是可能的。

Tabas说，与此同时，另外有一条经过很好试验过的方法。虽然我们掌握的动脉粥样硬化知识可能在变，但是最好的选择仍然是健康的饮食、充足的运动、监测胆固醇和血压。

在缺乏CHOP小鼠的早期动脉粥样硬化病变里减少凋亡和斑块的坏死。

细胞代谢学，9卷，5期，474-481，2009年5月6日

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Study Shows Why Some Artery Plaques Are Deadlier Than Others
A new US study found why a very small proportion of arterial plaques become deadly and lead to heart attack or stroke and why the vast majority others stay benign and apparently do no harm.

The study was the work of researchers at Columbia University Medical Center, and New York University Medical Center, both in New York, and is published in the 6 May issue of Cell Metabolism.

The researchers said that many people are wrong to believe that all arterial plaques inevitably result in heart attack or stroke and their study found out why so few of them are actually worth worrying about.

They also found an important protein that may be responsible for benign plaques turning into dangerous one.

While most atherosclerotic lesions are harmless, only about 2 per cent of them will eventually cause an acute and often fatal blood clot that leads to heart attack, sudden death or stroke, said the researchers.

What distinguishes a dangerous plaque from a benign one is the "billion dollar question" said Dr Ira Tabas, who is Richard J Stock Professor and Vice Chairman of Research, at the Department of Medicine at Columbia University and Professor of Medicine and Anatomy and Cell Biology.

Plaques or atherosclerotic lesions, are fatty, inflamed deposits that form on the inside walls of arteries. These deposits also collect white blood cells known as macrophages and the lesions build up at various spots along blood vessel walls, said Tabas, adding that it is not the size of the deposit but what lies beneath the surface that makes it a dangerous one.

He likened it to the magma or molten lava inside a volcano: rumblings in the core, which in the case of arterial plaques is made of dead cells, can erupt, and once a plaque ruptures it can form a blood clot in the lumen or the interior space of the artery through which the blood flows.

Their finding supports the idea that so-called endoplasmic reticulum (ER) stress together with the body's natural way of coping with that stress is one reason why the rupture takes place.

The ER of a cell does two things: it makes, folds and transports new proteins; and it controls the storage and release of the cell's store of calcium.

When something disturbs the cell's normal operation, it kicks into action a pathway called the unfolded protein response (UPR) which triggers cell suicide in those cells that are particularly stressed. The trigger for cell suicide is an ER stress effector conveniently called CHOP.

Tabas said it's OK for cells to die as long as they don't do so in large numbers. The ER pathway, when it works well, protects the whole organism, killing a a few cells here and there, But more and more scientists are beginning to realize that ER stress and the body's "overexuberant" reaction to it are common features of underlying neurodegenerative disease, aging, and diabetes, he said.

While earlier studies had suggested a link between ER stress and vulnerable plaques, this is the first to show a clear causal link between the two, said Tabas.

"It is this sudden clotting that restricts blood flow and can cause a heart attack, stroke, or sudden cardiac death," said Tabas, explaining that in our modern world most people have atherosclerosis by the time they reach the age of 20, and the challenge for the future will be stopping the harmless lesions in young people from becoming dangerous ones, or as he put it "soothing dangerous plaques so they don't rupture as we age".

Tabas said it was not obvious how to do that yet. There could be many reasons why plaques turn from benign to dangerous, but one of these is definitely linked to the presence of dead cells inside them, the necrotic core as the researchers termed it.

The dead cells release substances that weaken to cap that covers the lesion and hence allow it to erupt and trigger the formation of a clot, said Tabas.

For the study, Tabas and colleagues fed two groups of mice bred to have atherosclerosis a diet high in fat and cholesterol for 10 weeks. One group of mice had the CHOP gene deleted while the other did not. The mice without the CHOP gene produced smaller plaques than those with CHOP. But more importantly, the mice without the CHOP gene also showed 50 per cent lower rates of cell death and plaque necrosis.

Repeating the experiment with another strain of atherosclerotic mice showed essentially the same result, they noted.

Although previous studies have pointed to ER stress and UPR before, Tabas said their result still surprised them, especially the size of the effect.

"The fact that we were able to isolate one gene encoding one protein with such a profound effect on plaque necrosis was a big surprise," he said.

They were surprised because they were expecting this to be just one of many processes at work, including some that might compensate for the loss of the CHOP gene.

Tabas said that finding this effect in mice could translate to real clinical benefits for humans.

The finding opens the possibility that drugs targeting the CHOP gene could silence ER cell stress and be an effective way of treating heart disease, the number one killer in the US.

While cholesterol busting drugs can reduce the number of plaques that deposit inside arteries, they don't work for everyone, and besides, the deposits start quite early in life, with fatty streaks appearing in our arteries in our teens and plaques appearing in our 20s.

"A therapy that prevents the deaths of these cells may be able to reduce the number of vulnerable plaques and prevent heart attacks and strokes in the 70 percent of people who aren't protected from cholesterol-lowering drugs," said Tabas.

However, it might be years before an effective therapy based on this discovery is generally available, said the researchers, but it may be possible to bypass the problem of cell death by persuading other cells inside the plaque to capture and eliminate the dead cells before they can cause eruption.

In the meantime, there is another, well tested way. Although our knowledge of atherosclerosis may be changing, the best option may not, it may still be to have a healthy diet, take plenty of exercise, and keep an eye on cholesterol and blood pressure, said Tabas.

"Reduced Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Apoe-/- and Ldlr-/- Mice Lacking CHOP."
Edward Thorp, Gang Li, Tracie A. Seimon, George Kuriakose, David Ron, Ira Tabas.
Cell Metabolism, Volume 9, Issue 5, 474-481, 6 May 2009
doi:10.1016/j.cmet.2009.03.003