[Effects of early digoxin treatment on hypoxia-induced pulmonary artery hypertension].
OBJECTIVE
To explore the effects of digoxin on hypoxia-induced pulmonary artery hypertension (PAH) and the possible mechanisms.


METHODS
A total of 48 Sprague-Dawley rats were randomly divided into 4 groups: normoxia control, normoxia+digoxin, hypoxia control and hypoxia+digoxin. The animals were exposed to chronic intermittent hypoxia (PO₂: (10.5 ± 0.5) %, 8:00-16:00) or room air for 21 days.Each rat received a daily intraperitoneal injection of either digoxin (1.0 mg × kg⁻¹ × d⁻¹) or an equal volume of vehicle, starting at the first day of hypoxia or normoxia. At Day 21, mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (RV/(LV+S)) and index of wall thickness of small pulmonary artery (WT% and WA%) among groups were compared. And in vitro the changes of pulmonary artery smooth muscle cells (PASMCs) proliferation were determined by methyl thiazolyl tetrazolium (MTT) assay. Migration assay was performed with a Transwell chamber.Real-time quantitative polymerase chain reaction (PCR) was performed to quantify the mRNA levels of smooth muscle cell phenotype markers such as smooth muscle-α-actin, calponin and smooth muscle 22α under normoxic or hypoxic conditions in the absence or presence of digoxin. And the protein expressions of matrix metalloproteinase (MMPs) were determined by Western blot.


RESULTS
Digoxin treatment significantly lowered mPAP, reduced WT% and WA% and right ventricular hypertrophy compared with those of the hypoxic group (mPAP: (27.3 ± 2.7) vs (38.5 ± 2.3) mmHg (1 mmHg = 0.133 kPa); RV/(LV+S): (30.9 ± 3.3)% vs (42.8 ± 2.6)%, WT%: (21.7 ± 3.6)% vs (39.3 ± 2.0)%; WA%: (56.3 ± 4.7)% vs (79.5 ± 5.7)%, all P < 0.05). And in vitro, digoxin restored the hypoxia-induced inhibition of the expression of smooth muscle cell phenotype markers and prevented the hypoxia-induced activation of MMPs in PASMCs.


CONCLUSIONS
Early digoxin therapy reduces pulmonary artery remodeling in hypoxia-induced PAH rat model and this effect is probably correlated with the inhibitions of proliferation, migration, phenotype switching and expression of MMPs induced by hypoxia in PASMCs.
Department of Cardiology, Zhongda Hospital of Southeast University Medical School, Nanjing 210009, China.
Gaoliang
G
Yan
Shengda
S
Hu
Qingjie
Q
Wang
Dong
D
Wang
Jing
J
Wang
Yong
Y
Qiao
Email: tangchengchun@medmail.com.cn.
Chengchun
C
Tang
Genshan
G
Ma
Yuchun
Y
Gu
D000818:Animals; D049109:Cell Proliferation; D004077:Digoxin / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia; D020782:Matrix Metalloproteinases / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004077:Digoxin; D020782:Matrix Metalloproteinases