组蛋白去乙酰化酶抑制剂SAHA对间歇性低氧引起的小鼠心肌损伤的保护作用

Protective effect of histone deacetylase inhibitor SAHA on intermittent hypoxia-induced myocardial injury in mice

目的探讨去乙酰化酶抑制剂SAHA对间歇性低氧引起小鼠心肌损伤的保护作用及机制。方法将雄性昆明小鼠分为正常氧(Sham)组、间歇性低氧(IH)组、正常氧SAHA干预(Sham+SAHA)组及间歇性低氧SAHA干预(IH+SAHA)组。IH组和IH+SAHA组的造模方案是将利用低氧舱,将小鼠放到其内,然后进行每天8h的间歇性低氧处理,造模时间一共4周。并在间歇性低氧进行处理的最后2周,每日造模前给予腹腔注射SAHA 50 mg/(kg·d)。实验第4周末,处死小鼠,计算小鼠心脏重量/体质量和心脏重量/胫骨长度比值,HE染色和VG染色观察心脏病理形态学改变,DHE染色观察小鼠心肌中活性氧物(ROS)含量。结果与Sham组相比,IH组小鼠心脏重量/体质量和心脏重量/胫骨长度比值、心肌细胞横截面积、心肌纤维化和心肌中ROS含量显著增加;组蛋白去乙酰化酶抑制剂SAHA干预可明显改善间歇性低氧引起的心肌损伤及ROS增加。结论组蛋白去乙酰化酶抑制剂SAHA通过抑制氧化应激改善间歇性低氧小鼠的心肌损伤。

Objective To investigate the protective effect and mechanism of suberoylanilide hydroxamic acid( SAHA),a histone deacetylase inhibitor,on intermittent hypoxia-induced myocardial injury in mice. Methods Male Kunming mice were randomly divided into normal oxygen( Sham) group,intermittent hypoxia( IH) group,Sham+ SAHA group and IH + SAHA group. The mice in IH group and IH + SAHA group were exposed to 4-weeks intermittent hypoxia,8 h daily. Intraperitoneal injection of SAHA [50 mg/( kg·d)]was given daily in the last 2 weeks of intermittent hypoxia. At the end of the fourth week of the experiment,the mice were sacrificed and the ratio of heart weight/body weight and heart weight/tibia length was calculated. The pathological changes of the heart were observed by HE staining and VG staining. The content of reactive oxygen species( ROS) in the myocardium was detected by DHE staining. Results Compared with Sham group,the ratio of heart weight/body weight and heart weight/tibia length,myocardial cell cross-sectional area,myocardial fibrosis and ROS in myocardium were significantly increased in IH group. Intervention with SAHA could significantly improve myocardial injury induced by intermittent hypoxia and ROS increase. Conclusion SAHA,a histone deacetylase inhibitor,can improve intermittent hypoxia-induced myocardial injury in mice by inhibiting oxidative stress.