Adrenomedullin And Regulates Collagen Synthesis Via ERK Activation

ObjectivesThe definition of pulmonary hypertension (PH) is a mean pulmonary artery pressure greater than average. The range of normal pulmonary artery systolic pressure is from 20 mmHg to 25mmHg for healthy people at rest. If the mean pulmonary artery pressure is greater than 20 mmHg, people consider it is pulmonary hypertension. The pathophysiology of PH includes increasing contraction of pulmonary arteries and pulmonary vascular structural remodeling. The former belongs to functional alteration, which is reversible. The pulmonary vascular structural remodeling is characterized by proliferation of vascular smooth muscle cell, muscularization of non-muscular pulmonary arery and deposition of extracellar matrix such as collagen on the pulmonary vascular walls. That is irreversible. Recently people found a new active peptide-adrenomedullin, which could exert long-term and potent hypotensive activity. Intravenously administered ADM decreased pulmonary vascular resistance in hypoxic pulmonary hypertension rats and patients with pulmonary hypertension, improved cardiac function. Later, people found its precursor:preproADM (propreadrenomedullin) which is cleaved into 4 active peptides by endogenous protease:Adrenomedullin (ADM),adrenotensin (ADT),proadrenomedullin N-terminal 20 peptide (PAMP),proADM45-92. As a vasodilator, ADM inhibits proliferation of VSMC. ADT could contract arteries, increase MAP and induce VSMC proliferation. In another experiment, the plasma ADM level increased markedly and ADT level decreased in hypertensive rats. Study showed that ADM possessed inhibitive activities on the two effects of ADT to different extents. ADM could inhibit VSMC proliferation induced by ADT. At the same time, ADM and ADT showed reciprocal inhibition of release. After the administration of ADM, plasma ADM level was higher and ADT level lower. The interactions between peptides which originate from the same precursor are termed as intramolecular regulation (IMR). IMR provides a new thought for making clear the influence of proADM peptides in the forming of left to right shunt pulmonary hypertension and pulmonary vessel remodeling.The objective of the present study is to investigate the influence of adrenomedullin and adrenotension on typeâ… andâ…¢collagen synthesis in cultured pulmonary artery smooth muscle cells, and to detect whether extracellular signal-regulated kinase-1 (ERK1) signal transduction pathway participate the process of pulmonary artery smooth muscle cells proliferation. The above investigation may provide strong proof for the pathophysiology mechanism of left to right shunt pulmonary hypertension and the saying of ADM could slow down pulmonary hypertension through cutting off MAPK signaling pathway.Material and methods:Pulmonary artery smooth muscle cells (PASMCs) were cultured for 72h with different concentration of ADM and ADT were added. In Brdu incorporation, we have observed the effect of ADM and ADT on the proliferation of PASMCs. By using immuofluorescens, we explored the activation of ERK signal pathway on the synthesis of typeâ… and typeâ…¢collagen.Results:ADM inhibit the proliferation of pulmonary artery smooth muscle cells (PASMCs), while ADT promote pulmonary artery smooth muscle cells proliferation most significantly on a concentration of 10-7mg/ml. ADM ngatively regulate collagen synthesis via ERK activation.Conclusions:We demonstrate ADM and ADR regulate collagen synthesis via ERK signal pathway. It may play important role in prevention and cure of pulmonary hypertension.