[Roles and signal pathways of adrenomedullin and adrenotensin in pulmonary remodeling due to left to right shunt in rats].
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Zhao
Cui-fen
CF
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.
Wang
Li-juan
LJ
Gao
Li
L
Chang
Ping
P
Xia
Wei
W
Wang
Rong
R
Sun
Ruo-peng
RP
D053607:Adrenomedullin / Q000096:biosynthesis*; D056151:Airway Remodeling; D000818:Animals; D006976:Hypertension, Pulmonary / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000378:metabolism*; D011652:Pulmonary Circulation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D010446:Peptide Fragments; C094997:adrenotensin; D053607:Adrenomedullin; D020928:Mitogen-Activated Protein Kinases