Effects and mechanism of oridonin on pulmonary hypertension induced by chronic hypoxia-hypercapnia in rats

• Published in: Chinese medical journal 2009-06, Vol.122 (12), p.1380-1387
• Main Authors: Wang, Liang-Xing, Sun, Yu, Chen, Chan, Huang, Xiao-Ying, Lin, Quan, Qian, Guo-Qing, Dong, Wei, Chen, Yan-Fan
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Apoptosis; Blotting, Western; Diterpenes, Kaurane - pharmacology; Hypercapnia - physiopathology; Hypertension, Pulmonary - drug therapy; Hypoxia - physiopathology; Immunohistochemistry; Male; Membrane Potential, Mitochondrial; Microscopy; Microscopy, Electron, Transmission; PASMC; Pulmonary Artery - drug effects; Random Allocation; Rats; Rats, Sprague-Dawley; 低氧高二氧化碳; 冬凌草甲素; 平均肺动脉压; 线粒体膜电位; 细胞凋亡指数; 肺动脉平滑肌细胞; 肺动脉高压
• ISSN: 0366-6999; 2542-5641
• DOI: 10.3760/cma.j.issn.0366-6999.2009.12.005

Background Pulmonary arterial hypertension （PAH） is characterized by suppressing apoptosis and enhancing cell proliferation in the vascular wall. Inducing pulmonary artery smooth muscle cells （PASMC） apoptosis had been regarded as a therapeutic approach for PAH. Oridonin can cause apoptosis in many cell lines, while little has been done to evaluate its effect on PASMC. Methods Thirty male Sprague-Dawley rats were randomly assigned to three groups： normal control （NC）; hypoxia-hypercapnia （HH）; Hypoxia-hypercapnia ＋ oridonin （HHO）. Rats were exposed to hypoxia-hypercapnia for four weeks. Cultured human PASMC （HPASMC） were assigned to three groups： normoxia （NO）; hypoxia （HY）; hypoxia ＋ oridonin （HO）. The mean pulmonary artery pressure, mass ratio of right ventricle over left ventricle plus septum （RV/（LV＋S））, the ratio of thickness of the pulmonary arteriole wall to vascular external diameter （WT%） and the ratio of the vessel wall area to the total area （WA%） were measured. Morphologic changes of pulmonary arteries were observed under light and electron microscopes. The apoptotic characteristics in vitro and in vivo were detected. Results The mPAP, RW（LV＋S）, WT%, and WA% in the HH group were significantly greater than those in the NC （P 〈0.01） and HHO groups （P 〈0.01）; the activities of caspase-3 and caspase-9, and the expressions of Bax, cyt-C and apoptotic index （AI） in the group HH were less than those in the NC and HHO groups; and the expression of Bcl-2 in group HH was greater than that in the NC and HHO groups. HPASMC mitochondrial membrane potentials in group HO was lower than in group HY （P 〈0.01）, and cyt-C in the cytoplasm, AI, and caspase-9 in the HO group were greater than that in the HY group （P 〈0.01）, but the expression of Bcl-2 in the HO group was less than that in the HY group （P 〈0.05）. Conclusions The results suggest that oridonin can lower pulmonary artery pressure effectively, and inhibit pulmonary artery structural remodeling by inducing smooth cell apoptosis via a mitochondria-dependent pathway.