All-trans retinoic acid in pulmonary vascular structural remodeling in rats with pulmonary hypertension induced by monocrotaline.
OBJECTIVE
To determine whether all-trans retinoic acid (atRA) exerts an inhibitory effect on rats with pulmonary hypertension induced by monocrotaline.


METHODS
All rats were given a single subcutaneous injection of either monocrotaline (60 mg/kg) or saline. Monocrotaline-injected rats received either atRA (30 mg.kg-1.day-1) or saline through oral-gastro intubation. On Days 7, 14, 21, and 28 respectively after monocrotaline injection, cardiovascular catheters were inserted to examine the mean pulmonary artery pressure of rats in each group. Meanwhile, the matrix metalloproteinase-1 (MMP-1) mRNA expression and hydroxyproline content in the main pulmonary artery were determined by RT-PCR and chromometry, respectively.


RESULTS
The mean pulmonary artery pressure of rats in the model group increased significantly on day 21 and reached a peak on Day 28 compared with the control group (25.7 +/- 4.3 mm Hg vs 15.1 +/- 1.5 mm Hg and 38.5 +/- 6.4 mm Hg vs 16.4 +/- 2.0 mm Hg, P < 0.01). MMP-1 mRNA overexpression was present on Day 14 (0.72 +/- 0.15 vs 0.39 +/- 0.08, P < 0.01) and was rapidly down-regulated on Day 21 and 28 compared with Day 14, but was still higher than that in the control. The hydroxyoroline content of the main pulmonary artery dropped significantly on Day 14 (4.01 +/- 1.13 micrograms/mg vs 5.10 +/- 0.91 micrograms/mg, P < 0.05) and increased significantly on Days 21 and 28 compared with the control. atRA inhibited the MMP-1 mRNA overexpression from Day 14 to Day 28 and reduced the hydroxyproline content (5.59 +/- 0.70 micrograms/mg vs 7.96 +/- 1.13 micrograms/mg and 7.77 +/- 0.96 micrograms/mg vs 9.93 +/- 1.27 micrograms/mg, P < 0.01) and the mean pulmonary artery pressure compared with the model group (19.6 +/- 3.2 mm Hg vs 25.7 +/- 4.3 mm Hg and 26.3 +/- 4.6 mm Hg vs 38.5 +/- 6.4 mm Hg, P < 0.01).


CONCLUSIONS
atRA inhibits MMP-1 overexpression and the accumulation of collagen, which might elicit favorable geometric remodeling in rat pulmonary hypertension induced by monocrotaline.
Qin
Y
Y
Shanghai Institute for Pediatric Medical Research, Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China.
Zhou
A
A
Ben
X
X
Shen
J
J
Liang
Y
Y
Li
F
F
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006909:Hydroxyproline / Q000032:analysis; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008168:Lung / Q000737:chemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000627:therapeutic use*
D012333:RNA, Messenger; D014212:Tretinoin; D016686:Monocrotaline; D020781:Matrix Metalloproteinase 1; D006909:Hydroxyproline