adrenomedullin and Airway-Remodeling

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary arterial remodeling and right ventricular failure. Despite recent advances in pathophysiological mechanism exploration and new therapeutic approaches, PAH remains a challenging condition. In this study, we investigated the roles of the peptide fragments from proadrenomedullin (proADM) such as adrenomedullin (ADM), adrenotensin (ADT), and proadrenomedullin N-terminal 20 peptide (PAMP) during pulmonary remodeling caused by high pulmonary blood flow, and probed the possible involvement of mitogen-activated protein kinase (MAPK) signal transduction pathways. Sixteen rat models of PAH were artificially established by surgically connecting the left common carotid artery to the external jugular vein. We subcutaneously injected an extracellular signal-regulated protein kinase (ERK1/2) inhibitor, PD98059, in eight rats, treated another eight rats with an equal volume of saline. Eight rats without connections served as the control group. We observed that mRNA expression levels of ADM, stress-activated protein kinase (SAPK), and ERK1/2 were significantly elevated in the shunted rats; furthermore, ERK1/2 levels were significantly inhibited by PD98059. Protein levels of ADM, PAMP, p-SAPK, and p-ERK1/2 were significantly higher ADT was lower, and p-p38 remained unchanged in the rat models compared with the controls. However, the protein expression of both ADM and p-ERK1/2 was significantly inhibited by PD98059. Our results suggest that levels of ADM, ADT, and PAMP respond to pulmonary remodeling, and that activation of the SAPK and ERK1/2 signaling pathways is involved in pulmonary hypertension and artery remodeling caused by high pulmonary blood flow.

Topics: Adrenomedullin; Airway Remodeling; Animals; Gene Expression; Hypertension, Pulmonary; Lung; Male; MAP Kinase Signaling System; Peptide Fragments; Protein Precursors; Pulmonary Circulation; Rats, Wistar; Regional Blood Flow; Vascular Remodeling

The effect of vascular active peptides on the development of pulmonary remodeling and pulmonary hypertension due to left to right shunt congenital heart diseases is the focus of today's studies. The present study was conducted to investigate the roles of adrenomedullin (ADM) and adrenotensin (ADT) in pulmonary remodeling due to left to right shunt in rat lungs.. Twenty-one male Wistar rats were divided into two groups randomly. A right common carotid artery to external jugular vein shunt operation was performed on experimental rats (n = 9) to establish a left to right shunt animal model. Meanwhile, the common carotid artery and external jugular vein of the control group rats (n = 12) were just isolated without connection. Twelve weeks later, the mean pulmonary artery pressure (mPAP), the right ventricle to left ventricle plus septum ratio [weight, RV/(LV + SP)], the percentage of media wall thickness (MT%) were calculated. The distributions and relative protein contents of ADM and ADT in lungs were measured by immunohistochemical staining and Western blotting analysis. The relative gene expression for ADM, ADT, p46-p54 stress-actived protein kinase (SAPK) and p44 extracellular signal-regulated protein kinase 1 (ERK(1)) were investigated by RT-PCR.. The muscular and the tunica intimae layer of pulmonary artery were thicker in experiment group rats than those of control group, and the mPAP increased significantly in shunt group [(27.10 +/- 6.67) mm Hg (1 mm Hg = 0.133 kPa)] compared with that in control group [(14.32 +/- 3.14) mm Hg] (t = 5.5507, P < 0.001). The ratios of RV/(LV + SP) and MT% increased significantly in experimental group in contrast to the control group (P < 0.001). ADM and ADT positive granules distributed mainly over vascular smooth muscle cells, and Western blotting and integrated optical density analysis showed that the content of ADM increased in shunt group rats (P < 0.001), however, ADT content decreased (P < 0.001). The mRNA expression of ADM, SAPK and ERK(1) up-regulated in experiment group compared with the control group (P < 0.01, and P < 0.001 respectively), however, the ADT mRNA expression decreased in experimental rats in contrast to the control group (P < 0.001).. The phenomenon of intramolecular regulation of ADM and ADT, which both derived from proadrenomedullin, existed in the development of pulmonary remodeling and pulmonary hypertension due to left to right shunt. The mitogen-activated protein kinases (MAPKs) signal transduction pathway has been activated in the formation of left to right shunt pulmonary remodeling and pulmonary hypertension, and ADM may slow down the occurrence of pulmonary hypertension through cutting off MAPKs signaling pathway.

Topics: Adrenomedullin; Airway Remodeling; Animals; Hypertension, Pulmonary; Lung; Male; Mitogen-Activated Protein Kinases; Peptide Fragments; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Signal Transduction

To explore the effect of adrenomedullin(1-50) (ADM(1-50)) on hypoxic pulmonary hypertension and pulmonary vascular structural remodeling and the plasma concentration of nitric oxide (NO) and hydrogen sulfide (H(2)S) in rats.. Twenty male Wistar rats were randomly divided into control group (n=7), hypoxic group (n=6) and hypoxic with ADM(1-50) group (n=7). ADM(1-50) was subcutaneously administered into rats of hypoxic with ADM(1-50) group by mini-osmotic pump (300 ng/h). After two weeks' hypoxic challenge, mean pulmonary arterial pressure (mPAP) was evaluated by using a right cardiac catheterization procedure. The ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV+S)] was detected. Pulmonary vascular microstructure was measured and the ultrastructural changes in intra-acinar pulmonary arteries were observed. Meanwhile, plasma concentrations of NO and H(2)S were measured.. mPAP was significantly increased in hypoxic rats than that in controls [(24.9+/-6.8) mmHg vs (14.3+/-2.4) mmHg, P<0.01,1 mmHg=0.133 kPa]; RV/(LV+S) was also significantly increased in hypoxic rats than that in controls [(0.318+/-0.054) vs (0.182+/-0.007), P<0.01]. Microstructure and ultrastructure of pulmonary arteries changed obviously in hypoxic rats with the development of hypoxic pulmonary vascular structural remodeling. Meanwhile, plasma NO and H(2)S concentrations in hypoxic rats were markedly decreased compared with controls. However, mPAP was significantly decreased in hypoxic rats treated with ADM(1-50) than that in hypoxic rats [(14.9+/-3.0) mmHg vs (24.9+/-6.8) mmHg, P<0.01]; RV/(LV+S) was also significantly decreased than that in hypoxic rats [(0.185+/-0.011) vs (0.318+/-0.054), P<0.01]. ADM(1-50) ameliorated pulmonary vascular structural remodeling of hypoxic rats in association with an increase in plasma NO and H(2)S concentrations.. ADM(1-50) plays an important role in regulation of the development of hypoxic pulmonary hypertension and hypoxic pulmonary vascular structural remodeling, through promoting NO and H(2)S production in hypoxic rats.

Topics: Adrenomedullin; Airway Remodeling; Animals; Chronic Disease; Hydrogen Sulfide; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide; Peptide Fragments; Pulmonary Artery; Rats; Rats, Wistar