Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Frontier Science Research Center, Faculty of Medicine, University of Miyazaki, Japan.
Peptides. 2019 Jan;111:47-54. doi: 10.1016/j.peptides.2018.03.012. Epub 2018 Mar 22.
Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or -independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.
肾上腺髓质素（adrenomedullin，AM）是一种从人嗜铬细胞瘤提取物中分离出的肽，由 52 个氨基酸组成，分子内有二硫键，羧基末端酰胺化。AM 存在于啮齿动物和人类的各种组织和器官中，包括心脏。在血浆和心肌中，肽浓度随着心脏肥大、急性心肌梗死和明显心力衰竭而增加。AM 在心血管系统中的主要功能是通过环腺苷酸依赖性或非依赖性机制舒张血管和利钠，从而调节血管张力。此外，AM 可能具有独特的特性，可抑制醛固酮分泌、氧化应激、细胞凋亡和刺激血管生成，从而保护心脏的结构和功能。AM 受体由降钙素受体样受体（calcitonin receptor-like receptor，CLR）和受体活性修饰蛋白（receptor activity-modifying protein，RAMP）2 或 3 组成的复合物，AM-CLR/RAMP2 系统对胚胎发育过程中心脏的发育至关重要。小规模临床试验已经证明了重组 AM 肽治疗心力衰竭的疗效和安全性。基因传递和延长天然肽半衰期的修饰 AM 肽可能是提高 AM 在临床环境中疗效和益处的创新方法。在这篇综述中，我们重点介绍了 AM 及其受体系统在心脏中的病理生理作用，并描述了 AM 和 proAM 衍生肽作为诊断生物标志物的进展，以及 AM 和修饰 AM 在心保护中的治疗应用。
