青蒿素通过HIF-1α/LDHA通路抑制糖酵解改善肺血管重塑

doi:10.3969/j.issn.1006-5725.2025.01.003

Abstract

Abstract:

Objective Aimed at investigating the effect and molecular mechanism of artemisinin on hemodynamics and vascular remodeling in monocrotaline（MCT） -induced pulmonary arterial hypertension （PAH） rats. Methods 30 male SD rats were randomly divided into 3 groups （n = 10）： control group， MCT-induced PAH group （MCT group， 60 mg/kg） and artemisinin intervention group （50 mg/kg）. At 28 days after modeling， the right ventricular systolic pressure （RVSP）， mean pulmonary artery pressure （mPAP）， heart rate and right ventricular hypertrophy index （RVHI） were measured to evaluate the development of PAH. HE staining and α-SMA immunohistochemistry were used to observe the morphology and assess muscularization of pulmonary arterioles， and the percentage of medial wall thickness （WT%），the percentage of vascular wall area （WA%） and the proportion of muscular vessels were calculated to evaluate the degree of pulmonary vascular remodeling. The mRNA and protein levels of HIF-1α and LDHA were detected by real-time PCR and Western blot， respectively. Pyruvate and lactate concentration in lung tissue was measured using pyruvate and lactateassay kit. Results Compared with the control group， the RVSP， mPAP， heart rate and RVHI were significantly increased in MCT-induced PAH rats （all P < 0.05）. Histological analysis showed that the increasedmedial wall thickness of small pulmonary arteries and vascular muscularization were observed in MCT-treated rats compared with control rats. WT%， WA% and muscularization degrees of pulmonary arterioles were higher in MCT-treated rats than those in the control group （all P < 0.05）， suggesting successful construction of PAH model. Compared with the MCT group， the RVSP， mPAP， heart rate and RVHI decreased in the rats treated with artemisinin（all P < 0.05）， accompanied with lower WT% and WA% （P < 0.05）， and muscularization of pulmonary arterioles was improved （P < 0.05）. Further study showed the mRNA and protein levels ofHIF-1α and LDHA in lung tissue of MCT-induced PAH rats were higher than those in the control group， the content of lactate and pyruvate and the ratio of lactate to pyruvate were higher than that in the control group （all P < 0.05）. However， the mRNA and protein levels of HIF-1α and LDHA in lung tissue of rats treated with artemisinin were lower than those in the MCT group， the content of lactate and pyruvate and the ratio of lactate to pyruvate were lower than that in the MCT group （all P<0.05）. Conclusion Artemisinin improves hemodynamic and pulmonary vascular remodeling in PAH rats through inhibiting HIF-1α/LDHA signaling pathway-mediated glycolysis.

Key words: pulmonary arterial hypertension, pulmonary vascular remodeling, artemisinin, glycolysis

CLC Number:

R543.2

Wenhua SHI,Yuqian CHEN,Yonghong ZHANG,Cong LI,Cui ZHAI,Ni YANG,Rui KE. A study of underlying mechanisms of artemisinin inhibiting glycolysis through HIF-1α/LDHA pathway to improve pulmonary vascular remodeling[J]. The Journal of Practical Medicine, 2025, 41(1): 15-22.

Figures/Tables 8

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References 26

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引物名称	核苷酸序列
HIF-1α	上游：5′-ACCTTCATCGGAAACTCCAAAG-3′
HIF-1α	下游：5′-ACTGTTAGGCTCAGGTGAACT-3′
LDHA	上游：5′-GTTGTTGGGGTTGGTGCTGT-3′
LDHA	下游：5′-TCGCCCTTGAGTTTGTCTTC-3′
β-actin	上游：5′-TTACTGCCCTGGCTCCTAG-3′
β-actin	下游：5′-CGTACTCCTGCTTGCTGATC-3′

组别	RVSP/mmHg	mPAP/mmHg	心率 /（次/min）	RVHI /%
对照组	19.56 ± 2.43	17.16 ± 1.96	254 ± 15	0.32 ± 0.05
MCT组	48.51 ± 3.21^*	37.16 ± 2.79^*	383 ± 19^*	0.56 ± 0.04^*
青蒿素干预组	31.02 ± 3.52^#	22.25 ± 1.80^#	278 ± 16^#	0.40 ± 0.03^#
F值	66.67	72.65	54.09	27.16
P值	0.000	0.000	0.000	0.001

组别	MT	WA	肌化程度
对照组	12.96 ± 3.47	16.27 ± 4.03	17.93 ± 3.10
MCT组	35.82 ± 4.89^*	42.15 ± 5.05^*	50.48 ± 4.66^*
青蒿素干预组	20.73 ± 2.96^#	30.06 ± 3.95^#	28.39 ± 4.52^#
F值	23.99	34.73	48.63
P值	0.001	0.001	0.000

组别	HIF-1α mRNA	LDHA mRNA	HIF-1α蛋白	LDHA蛋白
对照组	1.00 ± 0.12	1.00 ± 0.13	1.00 ± 0.17	1.00 ± 0.09
MCT组	1.94 ± 0.14^*	1.73 ± 0.16^*	2.12 ± 0.19^*	1.85 ± 0.10^*
青蒿素干预组	1.25 ± 0.10^#	1.19 ± 0.15^#	1.16 ± 0.20^#	1.31 ± 0.11^#
F值	24.52	18.67	44.19	32.68
P值	0.000	0.001	0.000	0.001

组别	乳酸/（mmol/L）	丙酮酸/（μmol/L）	乳酸/丙酮酸
对照组	0.88 ± 0.16	58.13 ± 6.73	15.18 ± 9.14
MCT组	1.91 ± 0.15^*	71.36 ± 8.92^*	26.86 ± 8.25^*
青蒿素干预组	1.13 ± 0.13^#	61.17 ± 9.24^#	18.55 ± 9.33^#
F值	53.01	25.18	38.42
P值	0.000	0.001	0.000

A study of underlying mechanisms of artemisinin inhibiting glycolysis through HIF-1α/LDHA pathway to improve pulmonary vascular remodeling

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