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ADM (adrenomedullin) is a multifunctional peptide isolated from human pheochromocytoma in 1993 by Japanese scholar Kitamura et al. human ADM gene is located at 11p15.4. This genomic DNA consists of 4 exons and 3 introns. The 5' end region contains the important TATA, CAAT and GC boxes. These components are responsible for the initiation of gene transcription. Basic expression is essential.
ADM Signaling Pathway
ADM-specific receptors can be activated through a variety of cell signal transduction pathways to achieve their biological functions, the most important cell signaling pathway is increasing the biological activity of adenylyl cyclase through the activation of Gs protein. Finally, it can increase the synthesis and secretion of second messenger cAMP in cells to exert biological functions or increase the biological activity of phospholipase C in vascular endothelial cells, thereby further increasing the levels of intracellular second messenger 1,4,5 - inositol trisphosphate (IP3) to achieve its many biological functions. ADM mainly increases the production of intracellular second messenger cAMP in vascular smooth muscle cells, which further causes vascular endothelial cells to release nitric oxide (NO), an intracellular signaling pathway, and finally achieves its biological role in dilating blood vessels and lowering blood pressure.
In isolated perfused kidneys of rats, endothelial-derived hyperpolarizing factor (EDHF) seems to be involved in P13 by opening the K+ channel. In addition, there are intracellular Ca2+ pathways, mitogen-activated kinase (MAPK) pathway and adenosine triphosphate (ATP)-dependent K+ pathway in rat aorta, ADM can induce epithelial-dependent vasodilation, and this biological function is achieved through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) intracellular signal transduction pathway. In studies of rat myocardial ischemia-reperfusion models, it was found that ADM has an important protective effect on myocardial ischemic-reperfused rat cardiomyocytes, and this protective function is also through PBK/AKT intracellular signal transduction. MAPK/ERKl/2 channels are also associated with ADM-induced epithelial vascular proliferation and cell proliferation in the rat adrenal bulb.
Figure 1. Summary diagram of the proposed adrenomedullin (ADM) signaling pathway in the retina. (Blom, et al. 2012).
The Physiological Function of ADM
ADM has many complex functions, including cell proliferation, contraction, migration, and interactions with other neuroendocrine factors. ADM circulates in plasma, and its exact role as a circulating hormone is unclear. The concentration of ADM in plasma is not directly measured because it has a half-life in plasma of only 22 minutes. The immunoreactive ADM in the plasma is actually derived from the enzymatically digested ADM with different biological activities. In addition, ADM is also known to bind to complement factor H in plasma. ADM plays an important role in the regulation of the water-electrolyte balance, and it can also inhibit the expression of atrial natriuretic peptide also in muscle cells. ADM regulates also the hypertrophy of muscle cells and the growth of fibroblasts. It also exerts antibacterial effects by binding to bacterial cell walls. In addition to regulating vascular tone, ADM also regulates vascular proliferation and remodeling.
ADM can inhibit the proliferation of vascular smooth muscle cells. This biological function is achieved by inhibiting platelet-derived growth factor (PDGF)-induced thymidine incorporation. This effect can reduce blood pressure and increase heart rate with increasing dose of ADM. In the process of studying the pathophysiological effects of ADM on renal cells, immunohistochemical techniques were used to find that ADM was localized in glomerular mesangial cells, capillary endothelial cells, vascular smooth muscle cells, and renal tubular epithelial cells. ADM can be produced by mesangial cells. ADM can inhibit the proliferation of glomerular mesangial cells, promote apoptosis, inhibit cell migration, inhibit oxidative stress, and promote glomerular mesangial cells to secrete hyaluronic acid, exerting a protective effect on the kidney. This biological effect may be mediated through cAMP intracellular signal transduction pathways. The expression of ADM in the stomach can regulate gastric acid secretion and change with fasting and starvation. After fast starvation, its expression is increased at the bottom of the stomach. After chronic starvation, it is increased at the euphoria. ADM regulates the ileal rhythm and inhibits its contraction, which may be mediated through activation of the ATP-dependent K+ channel by the β3 adrenergic receptor and protein kinase A.
ADM and Cancer
Larráyoz et al. found that under certain conditions, high ADM levels returned to normal after surgical removal of the tumor, suggesting that the tumor is a source of ADM overproduction. Since ADM acts as an autocrine/paracrine growth factor, it prevents apoptosis-mediated cell death, increases tumor cell motility and metastasis, induces angiogenesis, and blocks immune surveillance by suppressing the immune system, so ADM expression in tumor cells has a good research perspective. The conclusion in the study of liver cancer is that the expression of ADM is certainly related to the invasion and progression of tumors. In patients with locally cleared lesions of renal clear cell carcinoma and colon cancer, high expression of ADM mRNA is associated with a recurrence risk of the disease. Zhou et al. explored the relationship between adrenomedullin (ADM) and epithelial-mesenchymal transition (EMT) in intrahepatic cholangiocarcinoma (ICC) and found that ADM plays an important role in the metastasis of ICC and the ADM signal of EMT. Conduction may represent a valuable therapeutic target in cancer patients. The mRNA levels of ADM and CLR are much higher in pancreatic carcinoma tissue than in normal pancreatic islet tissue.
Stromal cell infiltration of bone marrow mononuclear cells is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and is associated with poor prognosis. Xu et al. found that ADM enhances the migration and invasion of bone marrow mononuclear cells through activation of MAPK, PI3K/Akt and eNOS signaling pathways. ADM also promotes adhesion and transendothelial migration of bone marrow mononuclear cells by increasing the expression of VCAM-1 and ICAM-1 in endothelial cells. In addition, ADM induces the pro-tumor phenotype of macrophages and bone marrow-derived suppressor cells (MDSCs). These results reveal new functions of ADM in PDAC and suggest that ADM is a promising target for the treatment of PDAC.
Diagnostic Application of ADM
Elevated levels of ADM in plasma is a sign of inflammation, which may be an important endocrine marker in inflammatory diseases. Di et al. demonstrated that the ADM signaling pathway may be impaired in the differentiation of myeloid leukemia cells into mature granulocytes or monocytes by modulating RAMPs/CRLR expression, PI3K/Akt cascade, and ERK/MAPK signaling pathways. In addition, pro-adrenomedullin, a more stable form of ADM and marker of cardiovascular disease, can be useful as a marker for identifying patients with a poor prognosis of acute myocardial infarction. The use of beta-adrenergic to block the sympathetic nervous system and mediators and block the renin angiotensin system have been shown to improve the function and prognosis of cardiovascular disease. Therefore, ADM may be increased to be a hormone system that is activated in cardiovascular disease.