Ishimitsu Toshihiko, Ono Hidehiko, Minami Junichi, Matsuoka Hiroaki
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan.
Pharmacol Ther. 2006 Sep;111(3):909-27. doi: 10.1016/j.pharmthera.2006.02.004. Epub 2006 Apr 17.
Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3'-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established.
肾上腺髓质素（AM）是一种血管舒张肽，最初从嗜铬细胞瘤组织中分离出来。然而，其信使核糖核酸（mRNA）在正常肾上腺、心脏、肾脏和血管中表达。人类AM基因位于11号染色体短臂，由4个外显子组成。在第1和第3内含子中有2个单核苷酸多态性，AM基因的3'端侧翼有一个胞嘧啶-腺嘌呤重复的微卫星标记，该标记与高血压和糖尿病肾病的发病风险增加有关。AM基因表达受多种刺激因素促进，包括炎症、缺氧、氧化应激、机械应激以及肾素-血管紧张素和交感神经系统的激活。AM基因启动子区域有几个转录因子的结合位点，包括白细胞介素-6表达核因子（NF-IL6）和激活蛋白2（AP-2）。此外，在包括高血压、心力衰竭和肾衰竭在内的各种心血管疾病患者中，血浆AM水平升高。这些发现表明AM在心血管疾病的发生或反应中起作用。事实上，实验和临床研究表明，全身输注AM可能对心肌梗死、心力衰竭和肾衰竭有治疗作用。此外，增强内源性AM生物活性的血管肽酶抑制剂可能使高血压和动脉硬化患者受益。最后，AM的血管生成和细胞保护特性可能在血管重建以及梗死心肌和缺血肢体中有用。由于AM具有潜在的临床益处，应确定其使用指征和最佳给药策略。
