尼可地尔对大鼠低氧性肺高压的影响

目的:探讨线粒体ATP敏感性钾通道开放剂(mitoKATPCO)尼可地尔(nicorandil)对大鼠低氧性肺动脉高压的影响。方法:将40只大鼠随机分成对照组(C组)、低氧组(H组)、低氧+尼可地尔组(N组)与低氧+尼可地尔+5-羟基葵酸盐组(HD组),后3组置于常压低氧仓内,每周6 d,每天8 h,持续4周后测定各组大鼠平均肺动脉压(mPAP),右心肥厚指数RV/(V+S),HE染色观察肺小动脉血管壁的病理变化并检测增殖相关抗原(PCNA)。结果:慢性缺氧可诱导大鼠mPAP及RV/(LV+S)升高,大鼠肺小血管增厚重构,PCNA表达增加,尼可地尔可显著抑制上述变化,且该效应可被线粒体KATP(mitoKATP)通道特异性阻断剂5-羟基葵酸盐阻断。结论:尼可地尔通过开放mitoKATP通道降低肺动脉压,拮抗右心肥厚,并抑制肺血管增殖重构,治疗低氧性肺高压。

埃他卡林通过c-JNK信号通路抑制缺氧诱导的人肺血管内皮细胞凋亡

目的:研究KATP通道开放剂埃他卡林在缺氧诱导的肺血管内皮细胞凋亡调节中的作用及机制。方法:细胞分组培养并经过药物及缺氧处理后,分别采用四甲基偶氮唑盐(MTT)法对细胞活性进行测定,同时采用Hoechst 33342染色法检测细胞凋亡,采用Western blot对JNK、磷酸化JNK、caspase-3等蛋白的表达进行检测。结果:缺氧可降低细胞活性,诱导肺动脉内皮细胞凋亡,而埃他卡林可抑制凋亡,这种细胞保护作用可被KATP拮抗剂5-HD阻断;埃他卡林可抑制缺氧引起的c-JNK通路的磷酸化激活,并抑制下游凋亡蛋白caspase-3的表达,与c-JNK抑制剂SP600125作用一致,而5-HD处理组的趋势则相反。结论:埃他卡林可通过开放KATP通道抑制缺氧诱导的肺动脉内皮细胞凋亡,这种保护机制涉及了对c-JNK通路及下游凋亡蛋白的调节。

Quercetin,the key constituent of Astragali Radix,modulates ferroptosis in PASMCs and attenuates hypoxia pulmonary hypertension via the MAPK signaling pathway

This study delved into the mechanism by which the principal component of Astragali Radix regulated ferroptosis in the context of hypoxia-induced pulmonary hypertension,employing a combination of network pharmacology and experimental validation techniques.Active constituents of Astragali Radix and their corresponding targets were identified using the TCMSP database,while therapeutic targets associated with hypoxia-induced pulmonary hypertension were sourced from the GeneCards database.The Venn online tool facilitated the identification of overlapping targets between the active constituents of Astragali Radix and hypoxia-induced pulmonary hypertension.Interaction network diagrams depicting the relationship between Astragali Radix’s active constituents and their targets were constructed using Cytoscape software,with core targets and sub-networks identified using the CytoHubba plug-in.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted using the DAVID database.Additionally,the FerrDb database was consulted to analyze genes implicated in regulating ferroptosis.The investigation revealed 18 active constituents selected from Astragali Radix,with quercetin emerging as the key component.A total of 35 potential targets associated with Astragali Radix in regulating ferroptosis and addressing hypoxia-induced pulmonary hypertension were predicted.Experimental validation demonstrated that quercetin could inhibit the MAPK signaling pathway,resulting in reduced Fe2+and lipid peroxide levels,increased GPX4 expression,and the reversal of ferroptosis.In summary,this study elucidated the fundamental constituents and pivotal signaling pathways through which Astragali Radix modulated ferroptosis and mitigated hypoxia-induced pulmonary hypertension.Specifically,quercetin,a core constituent of Astragali Radix,was observed to inhibit ferroptosis in pulmonary arterial smooth muscle cells via the MAPK pathway and alleviate hypoxia-induced pulmonary hypertension.

Acute effect of tetrandrine pulmonary targeting microspheres on hypoxic pulmonary hypertension in rats

Objective To assess the effect of tetrandrine (Tet) pulmonary targeting microspheres on hypoxic pulmonary hypertension and evaluate its selective action on pulmonary circulation.Methods Twenty rats were exposed to hypoxic conditions for 3 weeks. Ten rats were used as normoxic controls. We administered Tet pulmonary targeting microspheres to 10 hypoxic rats and Tet aqueous solution to 10 hypoxic rats and the 10 control rats. Mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization, and mean systemic blood pressure (mSBP) was measured by left femoral catheterization. Results Rats exposed to hypoxia developed pulmonary hypertension. The decrease in mPAP in rats treated with Tet pulmonary targeting microspheres was significantly greater than that in rats receiving Tet aqueous solution (P【0.05), and the effects were longer with Tet pulmonary targeting microspheres. Moreover, Tet pulmonary targeting microspheres, unlike Tet aqueous solution, did not decrease mSBP.Conclusion Tet pulmonary targeting microspheres were more effective than Tet aqueous solution in treating hypoxic pulmonary hypertension and acted selectively on the pulmonary circulation.

Expression of adrenomedullin and its receptor in lungs of rats with hypoxic pulmonary hypertension

OBJECTIVE: To investigate the role of adrenomedullin (AM) in the development of hypoxic pulmonary hypertension (HPH), and to assess the expression of AM and adrenomedullin receptor (AMR) in the lungs of rats with HPH. METHODS: We exposed 10 rats to normobaric hypoxic conditions for 3 weeks to establish rat model of pulmonary hypertension; and 10 other rats were used as normoxic controls. Mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization. The thickness of pulmonary arterioles was measured by a computerized image analyzer. We used the reverse transcription-polymerase chain reaction (RT-PCR) to assess the change of expression of AM and AMR in lung of HPH rat model. RESULTS: Compared with the control group, hypoxic rats developed remarkable pulmonary hypertension, increment in the thickness of pulmonary arterioles and right ventricular hypertrophy (P