[Expression of adrenomedullin and its receptor in lungs of rats with hypoxia-induced pulmonary hypertension].
OBJECTIVE
To investigate the effect and mechanism of the changes of adrenomedullin (ADM) and its receptor (ADMR) mRNA in the process of hypoxia pulmonary hypertension (HPH).


METHODS
Thirty male Wistar rats were randomly divided into five groups: one control group and 4 hypoxia groups (3 d, 7 d, 14 d, 21 d). Rats in the hypoxia groups were exposed to hypoxia for 3 d, 7 d, 14 d, and 21 d respectively. The mean pulmonary arterial pressure (mPAP) and right ventricular hypertrophy index (RVHI) were measured, and hypoxic pulmonary vascular remodeling (HPSR) was observed with morphometric analysis. Semiquantitative in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to measure the expression of ADM and ADMR mRNAs in pulmonary artery walls and lung tissue. Inducible nitric oxide synthase (iNOS) was determined.


RESULTS
(1) The level of mPAP (22.7 +/- 2.8) mm Hg, the ratio of vascular wall thickness to external diameter (MT%) (46 +/- 4)% and the ratio of vascular wall area to the total area (MT%) [(55 +/- 6)%] were significantly higher in the hypoxia 7 d group than those in the control group [(16.4 +/- 1.4) mm Hg, (35 +/- 3)% and (42 +/- 5)% respectively] (P < 0.01). These parameters reached a high-level stable phase on hypoxia 14 d; RVHI was significantly higher [(26.5 +/- 2.9)%] on hypoxia 14 d than in the control group [(22.9 +/- 2.2)%] (P < 0.01); (2) In situ hybridization showed that ADM and ADMR mRNAs were expressed dynamically in pulmonary arterial endothelial cells (PAEC) and ectoblast cells after hypoxia. In PAECs the expressions of ADM (6%) and ADMR (8%) were lower on hypoxia 3 d than in the control group (23%, 27%) (P < 0.01); but increased on hypoxia 7 d (33%, 52%). The expression level reached its peak on 14 d and remained at a high level on 21 d. In the ectoblast cells, ADM mRNA (42%) and ADMR mRNA (46%) were significantly higher in the hypoxia 7 d group than that in the control group (19% and 21%, respectively, P < 0.01), which further reached a high level on 14 d and 21 d; (3) RT-PCR showed that ADM mRNA (0.43 +/- 0.48) and ADMR mRNA (0.32 +/- 0.38) in the lung tissue were lower in the hypoxia 3 d group than those in the control group (0.69 +/- 0.10 and 0.48 +/- 0.05 respectively), but increased on 7 d (0.76 +/- 0.52) and (0.70 +/- 0.50). There was no difference in ADM mRNA between the hypoxia 7 d group and the control group, but the ADMR level in the hypoxia 7 d group was higher than the control (P < 0.01), with a maximum expression on 14 d and 21 d. iNOS mRNA increased significantly in the hypoxia 7 d group (1.21 +/- 0.44) as compared to the control group (1.05 +/- 0.17) (P < 0.01). There was a positive correlation between ADM or ADMR and iNOS (r = 0.893, 0.906, P < 0.01).


CONCLUSIONS
ADM as an autocrine/paracrine factor may play an important protective role in the development of HPH.
Xu
Ping
P
Laboratory of Respiratory, Third Affiliated Hospital, Nanhua University, Hengyang 421900, China.
Dai
Aiguo
A
Zhou
Houde
H
D053607:Adrenomedullin; D000818:Animals; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D010455:Peptides / Q000235:genetics*; D011651:Pulmonary Artery / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D010455:Peptides; D012333:RNA, Messenger; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin