The effect of halofuginone on cardiopulmonary function and its mechanism in rats with high-altitude pulmonary hypertension

doi:10.11958/20220965

Abstract

Abstract:

Objective To investigate the effect of halofuginone (HF) on the cardiopulmonary function of rats with high-altitude pulmonary hypertension (HAPH) and its mechanism. Methods Forty male SD rats were selected according to random number table method and divided into the model group, the low-dose, the medium-dose and the high-dose groups, with 10 rats in each group. HAPH rat model was constructed in hypobaric hypoxia chamber simulating altitude of 6 000 m. The other 10 were fed outside the cabin as the control group. Low, medium and high dose groups were given HF (0.5, 1 and 2 mg/kg, respectively). The model group and the control group were given distilled water, once a day, for consecutive 4 weeks. The mean pulmonary artery pressure (mPAP) was measured. The right ventricular hypertrophy index (RVHI) was calculated, and the degree of pulmonary vascular remodeling was assessed by hematoxylin-eosin (HE) staining. The levels of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in serum and lung tissue of rats were detected by enzyme-linked immunosorbent assay (ELISA). Results Compared with the control group, the mPAP and RVHI were significantly increased in the model group (P<0.05). The small pulmonary artery wall was significantly thickened and the lumen was narrowed, and levels of HIF-1α, VEGF and ET-1 in serum and lung tissue were significantly increased (P<0.05). Compared with the model group, the mPAP and RVHI were significantly decreased in the low, medium and high dose groups (P<0.05). The degree of pulmonary vascular remodeling was significantly alleviated in the medium and high dose groups, and levels of HIF-1α, VEGF and ET-1 in serum and lung tissue were significantly decreased, while levels of VEGF and ET-1 in lung tissue were only decreased in the low-dose group (P<0.05). Compared with the low-dose group, the mPAP, VEGF and ET-1 in lung tissue were significantly decreased in the medium and high dose groups (P<0.05). Compared with the medium-dose group, there was no significant difference in each index in the high-dose group. Conclusion HF can reduce the mean pulmonary artery pressure, relieve right ventricular hypertrophy and improve pulmonary vascular remodeling in HAPH rats, and its mechanism may be related to the inhibition of HIF-1α, VEGF and ET-1 expressions.

Key words: DICHROA FEBRIFUGA, ketones, altitude, hypertension, pulmonary, vascular endothelial growth factors, endothelin-1, HIF-1α

CLC Number:

R563

Figures/Tables 3

References 19

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组别	mPAP（mmHg）	RVHI（%）
对照组	15.16±0.48	22.93±1.79
模型组	37.48±0.71^a	54.29±4.90^a
低剂量组	32.00±0.76^b	45.08±5.28^b
中剂量组	23.57±3.17^bc	41.52±5.59^b
高剂量组	22.79±1.79^bc	39.47±2.34^b
F	259.020^＊＊	71.012^＊＊

组别	mPAP（mmHg）	RVHI（%）
对照组	15.16±0.48	22.93±1.79
模型组	37.48±0.71^a	54.29±4.90^a
低剂量组	32.00±0.76^b	45.08±5.28^b
中剂量组	23.57±3.17^bc	41.52±5.59^b
高剂量组	22.79±1.79^bc	39.47±2.34^b
F	259.020^＊＊	71.012^＊＊

组别	HIF-1α		VEGF		ET-1
组别	血清	肺组织	血清	肺组织	血清	肺组织
对照组	97.44±4.24	101.54±12.62	1 746.67±127.37	1 236.67±139.87	357.27±7.11	315.45±33.27
模型组	137.82±10.26^a	153.85±10.76^a	2 426.67±242.80^a	1 733.33±89.39^a	500.00±61.54^a	460.91±38.63^a
低剂量组	128.59±12.65	146.54±9.39	2 315.00±165.93	1 488.33±103.13^b	463.64±29.38	400.91±19.40^b
中剂量组	116.79±9.07^b	129.36±7.29^b	1 935.00±121.02^b	1 336.67±116.32^bc	394.09±38.70^b	359.55±30.23^bc
高剂量组	111.41±12.27^b	115.90±17.67^b	1 886.67±127.22^b	1 281.67±88.30^bc	374.09±19.62^b	331.36±36.82^bc
F	23.533^＊＊	31.739^＊＊	32.135^＊＊	34.113^＊＊	28.469^＊＊	32.724^＊＊

组别	HIF-1α		VEGF		ET-1
组别	血清	肺组织	血清	肺组织	血清	肺组织
对照组	97.44±4.24	101.54±12.62	1 746.67±127.37	1 236.67±139.87	357.27±7.11	315.45±33.27
模型组	137.82±10.26^a	153.85±10.76^a	2 426.67±242.80^a	1 733.33±89.39^a	500.00±61.54^a	460.91±38.63^a
低剂量组	128.59±12.65	146.54±9.39	2 315.00±165.93	1 488.33±103.13^b	463.64±29.38	400.91±19.40^b
中剂量组	116.79±9.07^b	129.36±7.29^b	1 935.00±121.02^b	1 336.67±116.32^bc	394.09±38.70^b	359.55±30.23^bc
高剂量组	111.41±12.27^b	115.90±17.67^b	1 886.67±127.22^b	1 281.67±88.30^bc	374.09±19.62^b	331.36±36.82^bc
F	23.533^＊＊	31.739^＊＊	32.135^＊＊	34.113^＊＊	28.469^＊＊	32.724^＊＊