Role of Adenosine in Response to Vascular Inflammation
Role of Adenosine in Response to Vascular Inflammation
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DOI：
10.1161/atvbaha.112.247874
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发表时间：
2012-04-01
影响因子：
8.7
通讯作者：
Linden, Joel
中科院分区：
文献类型：
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作者：
Linden, Joel
腺苷的第一个已知功能是作为能量产生的生物化学中的中心因子。也许由于这种作用，它也进化为一种信号分子，将代谢应激和组织损伤与4 G蛋白偶联腺苷受体的激活联系起来。对腺苷生理学的早期认识早于腺苷信号传导的细胞生物学发现的几十年。腺苷的第一个公认的生理活性是“心脏跳动的干扰”，最初是在1929年由德鲁里和圣捷尔吉在剑桥大学进行的一项非常出色的研究中描述的。[1]在此之前的34年，罗伯特·伯恩（Robert Berne）首次阐明了腺苷负责“冠状动脉血流的代谢调节”。20世纪80年代和90年代，腺苷受体被鉴定出来，选择性激动剂和拮抗剂出现，在确定心脏和血管组织上腺苷受体亚型的身份和功能方面取得了快速进展。在此期间，人们还意识到在所有细胞类型上都发现了1个或多个腺苷受体，并且它们的功能多种多样。近年来，腺苷信号传导领域已经超越了腺苷对心血管的直接影响的问题，并集中在更复杂的问题上：腺苷在胚胎发育和对慢性炎症性疾病的反应中的作用是什么，这些疾病通常与非常高的组织水平的积累有关？在这卷的一系列评论集中在新认识的作用，腺苷在胚胎发育和血管病理生理学。还值得注意的是，腺苷受体在各种组织上的表达，以及参与腺苷产生的酶（如CD73）的表达并不像曾经认为的那样是恒定的，而是现在已知受到某些细胞因子、病原体和缺氧的高度转录调节。因此，现在人们认识到，在慢性疾病中，腺苷的产生和腺苷受体的表达都发生了重大变化。在他们关于勃起功能控制的文章中，温和夏比较和对比了主要血管扩张剂一氧化氮和腺苷在健康和疾病中的作用。这篇文章旨在说明腺苷的过度生产或生产不足都可能导致病理学。该综述还提醒人们，腺苷仍然是血流的关键生理调节剂，而不考虑将注意力集中在一氧化氮作为另一种血管扩张信号分子上。腺苷产生通常用于保护应激组织免受损伤，但腺苷过度产生可导致异常勃起中发生的病理。腺苷的另一个新发现的重要作用是对胚胎发育的影响。Riverly和Wendler总结了最近的研究结果，表明胚胎中腺苷信号的中断，特别是在缺氧期间，会导致心脏功能的变化，并持续到成年期。有趣的是，他们还确定咖啡因，一种广泛使用的腺苷受体拮抗剂，可能对胎儿有危险。这强调了组织应激过程中产生的腺苷在参与保护细胞免受损伤的过程中起着至关重要的作用。
The first known function of adenosine was as a central factor in the biochemistry of energy production. Perhaps as a result of that role, it also evolved as a signaling molecule that links metabolic stress and tissue damage to the activation of 4 G protein coupled adenosine receptors. An early appreciation of the physiology of adenosine preceded by many decades the discovery of the cell biology of adenosine signaling. The first recognized physiological activity of adenosine was “disturbance of the heart beat” initially described in a remarkably elegant study for the year 1929, conducted at the University of Cambridge by Drury and Szent-Györgyi. 1 This preceded by 34 years the realization, first articulated by Robert Berne, that adenosine is responsible for the “metabolic regulation of coronary blood flow.” 2 Once adenosine receptors were identified in the 1980’s and 1990’s and selective agonists and antagonists became available, rapid progress was made in pinpointing the identity and function of adenosine receptor subtypes on cardiac and vascular tissues. During that time it was also realized that 1 or more adenosine receptors are found on all cell types and their functions are numerous. In recent years the field of adenosine signaling has moved beyond questions of direct cardiovascular effects of adenosine and focused on more complex questions: What are the roles of adenosine in embryonic development and in responses to chronic inflammatory diseases that are often associated with the accumulation of very high tissue levels? The series of reviews in this volume focus on newly appreciated roles of adenosine in embryonic development and vascular pathophysiology. It is notable also that the expression of adenosine receptors on various tissues, and the expression of enzymes that are involved in adenosine production, such as CD73, are not constant, as once thought, but are now known to be highly transcriptionally regulated by certain cytokines, pathogens, and hypoxia. Thus, it is now appreciated that in chronic diseases, both the production of adenosine and the expression of adenosine receptors undergo major changes.In their article about the control of erectile function, Wen and Xia compare and contrast the roles of the major vasodilators, nitric oxide and adenosine, in health and disease. The article serves to illustrate that either overproduction or underproduction of adenosine can produce pathology. The review also serves as a reminder that adenosine remains a key physiological regulator of blood flow, irrespective of the attention focused on nitric oxide as another vasodilator signaling molecule. Adenosine production normally serves to protect stressed tissues from injury, but adenosine overproduction can contribute to pathology as occurs in priapism. Another newly appreciated important effect of adenosine is on embryonic development. Rivkees and Wendler summarize recent findings demonstrating that disruption of adenosine signaling in embryos, particularly during hypoxia, produce changes in cardiac function that persist into adulthood. Interestingly, they also identify caffeine, a widely consumed adenosine receptor antagonist, as possibly dangerous to the fetus. This emphasizes the point that adenosine produced during tissue stress plays a critically important role in engaging processes to protect cells from injury.