糖尿病引起动脉粥样硬化机制阐明

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Study details how diabetes drives atherosclerosis

Researchers have discovered how diabetes, by driving inflammation and slowing blood flow, dramatically accelerates atherosclerosis, according to research to be published in the March 14 edition of the journal Circulation Research.

Experts once believed that atherosclerosis, or hardening of the arteries, developed when too much cholesterol clogged arteries with fatty deposits called plaques. When blood vessels became completely blocked, heart attacks and strokes occurred. Today most agree that the reaction of the body's immune system to fatty build-up, more than the build-up itself, creates heart attack risk. Immune cells traveling with the blood mistake fatty deposits for intruders, akin to bacteria, home in on them, and attack. This causes inflammation that makes plaques more likely to swell, rupture and cut off blood flow.

Making matters worse, nearly 21 million Americans have diabetes, a disease where patients’ cells cannot efficiently take in dietary sugar, causing it to build up in the blood. In part because diabetes increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke.

Past work has shown that high blood sugar has two effects on cells lining blood vessels as part of atheroslerosis. First, it increases the production of free radicals, highly reactive molecules that tear about sensitive cell components like DNA, causing premature cell death (apoptosis). This process also reduces the availability of nitric oxide (NO), which would otherwise enable blood vessels to relax and blood flow to increase.

In contrast to diabetes, exercise and good diet bring about faster blood flow through blood vessels. The force created by fast, steady blood flow as it drags along blood vessel walls has been shown by recent studies to protect arteries from atherosclerosis. Physical force has emerged recently as a key player in bodily function, capable of kicking off biochemical processes (e.g. weightlifting thickens bone).

“Inflammation is blood vessels is one of the main drivers of atherosclerosis, and diabetes makes it much worse,” said Jun-ichi Abe, M.D., Ph.D., associate professor with the Aab Cardiovascular Research Center at the University of Rochester Medical Center, and a study author. “Our study argues that a pathway surrounding a key signaling enzyme both protects the heart in normal cases, and is sabotaged by the chemicals produced in diabetes. We believe we have found a new therapeutic target for the treatment of diabetes-related damage to blood vessels.”

How Diabetes Does It

In people without diabetes, fast blood flow triggers an enzyme called extracellular signal-regulated kinase 5 (ERK-5). ERK5 in turn signals endothelial nitric oxide synthase (eNOS) to produce more nitric oxide and dilate blood vessels. It also activates Kruppel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor-g (PPARg), both of which block the ability of pro-inflammatory immune cells to home in on and adhere to diseased portions of blood vessels.

Past studies had shown diabetes to worsen atherosclerosis, but its exact link to related inflammation had remained unclear. The current results provides the first mechanistic description of how diabetes takes away the ability of fast blood flow force to protect blood vessels, arguing that it does so by interfering with ERK5 and its signaling partners.

Abe’s team showed that molecules called advanced glycation end products (AGEs), produced in greater levels by patients with diabetes, interfere with ERK5 cardioprotection. Glycation reactions cause the release of oxidizing side products like hydrogen peroxide (H202) that drive free radical production, inflammation and cell damage in many diseases.

Researchers found that AGEs and H202 sabotage ERK5 by encouraging the attachment to it of a small ubiquitin-related modifier (SUMO), a protein tag used by cells to fine-tune their control over proteins. In normal function, a cell may extend a protein’s lifespan, or send it from one part of the cell to another, by attaching a SUMO tag. In the current study, researchers found that AGEs and H202 induced ERK5-SUMOylation as part of disease. In addition, the team found that ERK5-SUMOylation was increased in the aortas of diabetic mice.

Along with Abe, Chang-Hoon Woo, Tetsuro Shishido and Carolyn McClain contributed to the work within the Aab Cardiovascular Research Center. Jae Hyang Lim and Jian-Dong Li within the Department of Microbiology & Immunology at the Medical Center contributed expertise, along with Jay Yang, professor of Anesthesiology at Columbia University. This work is supported by grants from the America Heart Association and the National Institutes of Health.

“Our experiments found that taking away the “SUMO tag” from ERK protects blood vessels against diabetes,” Abe said. “We believe that the SUMOylation of ERK turns off ‘good’ genes that are important in countering atherosclerosis. In the next phase, we will be looking for drug candidates that can turn on ERK5 as diabetes attempts to shut it down.”

Source: University of Rochester
在将要3月14日发表在《the journal Circulation Research》的文章中，研究者们目前已经发现了糖尿病是如何通过引起炎症反应、减慢血流以产生使动脉粥样硬化加速发展的原理。
研究者们曾经认为，动脉粥样硬化或者说动脉壁变厚是由于太多的胆固醇与脂质代谢产物形成的斑块堆积在血管壁上造成的。当血管被完全堵塞后，就会发生心梗或者脑梗。目前，大多数人们认为机体免疫系统对于脂肪生成过程的反应，而不是生成过程本身，会增加心梗的风险。免疫细胞跟随着血流中错误的脂质代谢产物流动，攻击那些与细菌相似的入侵者，在它们中定植，并攻击它们。这些炎症反应造成了斑块继续长大、破裂、堵塞血流。
更麻烦的是，美国有2100万人患有糖尿病，患有这种疾病的人身体不能吸收食物中的糖，因而造成过多的葡萄糖在血液中堆积。一部分原因是由于糖尿病会提高与动脉粥样硬化相关炎症的发生，糖尿病患者患心梗或者脑卒中的比率是正常人群的2倍。
过去的研究已经证实了高血糖对在造成动脉粥样硬化中对于血管内皮细胞有2方面的影响。首先，它造成了自由基生成的增加，激活一些分子造成细胞中敏感物质如DNA等的损伤，因而造成了细胞过早的凋亡。这一过程同样使得NO这一修复血管壁并且加速血流的物质活性的下降。
与糖尿病相反，运动以及良好的饮食习惯可以使血流加速。目前的研究显示，稳定、快速的血流可以保护血管，防止其发生动脉粥样硬化。现在，机械力在维持人体功能中的作用已经越来越受到人们的关注，甚至有取代化学过程的趋势。（例如减肥对减弱骨骼的作用）
文章作者Jun-ichi Abe, M.D., Ph.D., Rochester大学医学院Aab心血管研究中心副教授，说： “血管壁的炎症是造成动脉粥样硬化的重要因素，糖尿病使得这一作用更加加剧。我们的研究关注一种关键的信号酶，这种酶起到保护心脏的作用，而在糖尿病患者中，这种酶会被糖尿病患者体内的化学物质所破坏。我们认为已经发现一种新的治疗糖尿病相关的血管损害的目标物质。
糖尿病是加速动脉粥样硬化的
在没有糖尿病的人群中，快速的血流会激活一种成为细胞外信号调控激酶5 (ERK-5)的物质。这种物质会加速血管内皮细胞硝化酶(eNOS)，以增加NO的产生以及血管的扩张。它同时也会激活Kruppel样因子2(KLF2)和过氧化物酶增殖子-激活受体-g (PPARg)，这两种物质都可以阻止炎症因子黏附并定植在受损的血管内皮处。
以往的研究已经显示了糖尿病会加速动脉粥样硬化的发生，但是糖尿病与其之间具体的关系却并不清楚。这项研究第一次揭示了糖尿病是怎样使得快速血流保护血管壁的能力失效的原理，即通过干扰ERK5及其信号传导通路中的各个部件进行的。
Abe的团队解释道，严重糖尿病病人体内的晚期糖基化终末化产物(AGEs)，干扰了ERK5的心血管保护作用，糖基化引发了氧化的副产物如自由基产物如过氧化氢(H202)，造成许多疾病中的细胞损伤。
研究者们发现，AGEs 和 H202通过激活一种小的泛素相关的物质(SUMO)—一种调控细胞生长的蛋白标签，使其与ERK5结合。在正常情况下，通过使用标签蛋白(SUMO)，细胞可以延长一种蛋白的寿命，或者使其从细胞的一个部位移动到另一部位。在目前的研究中，研究者们发现了AGEs 和H202诱导的ERK5-SUMO结合物的产生是疾病发展中的一部分。同时，研究组发现ERK5-SUMO结合物在糖尿病大鼠的主动脉中含量增加。
Rochester大学医学院Aab心血管研究中心的Chang-Hoon Woo, Tetsuro Shishido 和Carolyn McClain也为这项研究做出了贡献，医学中心微生物学与免疫学系的Jae Hyang Lim 和Jian-Dong Li以及哥伦比亚大学麻醉学系的Jay Yang提供了专业的指导。这项研究是由美国心脏病学会以及NIH提供的。
Abe说：“我们的研究发现了清除ERK上结合的“SUMO 标签”可以保护血管免受糖尿病的伤害，我们相信与SUMO结合的ERK使得那些保护血管，避免产生动脉粥样硬化的基因失去了作用。下一步，我们将要开始研究找出那些能恢复被糖尿病损伤的ERK5的作用的药物。”