Farnesoid-X-receptor blockade reduces myocardial reperfusion injury in cholesterol-fed apolipoprotein E knockout mice
10.3760/cma.j.issn.0253-3758.2013.08.004
- VernacularTitle:类法尼醇X受体拮抗剂可减轻高脂载脂蛋白E基因敲除小鼠心肌缺血再灌注损伤
- Keywords:
Myocardial reperfusion injury;
Hyperlipidemias;
Farnesoid-X-receptor
- From:
Chinese Journal of Cardiology
2013;41(8):642-646
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effect of farnesoid-X-receptor (FXR) antagonist Zguggulsterone in an in vivo high-fat fed apolipoprotein E knockout (ApoE-/-) mice model of myocardial ischemia/reperfusion (I/R).Methods Male ApoE-/-mice were randomly divided into three groups:standard ApoE-/-group (fed with standard mouse diet for 12 weeks before myocardial I/R procedure,n =18),high-fat ApoE-/-group (fed with high-fat mouse diet for 12 weeks before myocardial I/R procedure,n =22),and high-fat ApoE-/-+ FXR antagonist group(fed with high-fat mouse diet for 12 weeks and received FXR antagonist Z-Guggulsterone 30 minutes before myocardial I/R procedure,n =17).The expression of FXR was detected by real-time quantitative-PCR.Myocardial infarct size was determined by Evans blue/TTC double staining methods.Myocardial apoptosis was determined by in situ TUNEL technique.Markers of the mitochondrial-mediated apoptotic pathway (cytochrome c release,caspase-9 activity,and BAX and BCL-2 levels),endoplasmic reticulum stress apoptotic pathway (caspase-12 activity and CHOP level),and death receptor apoptotic pathway (caspase-8 activity,and Fas and FasL levels) were also measured.Result FXR expression (3.7-fold higher,P ＜ 0.01),myocardial infarct size [(62.1 ±7.0)％ vs.(33.8 ±5.8)％,P＜0.01] and myocardialapoptosisindex[(36.8 ±5.7)％ vs.(17.2±3.8) ％,P ＜ 0.01] were all significantly higher in high-fat ApoE-/-group than those in standard ApoE-/-group.Compared with high-fat ApoE-/-group,myocardial infarct size [(24.4 ± 4.7) ％ vs.(62.1 ±7.0)％,P＜0.01] and myocardial apoptosis index [(13.8 ±2.7)％ vs.(36.8 ±5.7)％,P＜0.01]were significantly reduced in high-fat ApoE-/-+ FXR antagonist group.Moreover,levels of mitochondrialmediated apoptotic pathway markers (cytochrome c release,caspase-9 activity,and BAX/BCL-2 levels) and endoplasmic reticulum stress apoptotic pathway markers (caspase-12 activity and CHOP level) were significantly lower in high-fat ApoE-/-+ FXR antagonist group than those in high-fat ApoE-/-group (all P＜0.01).Levels of death receptor apoptotic pathway markers (caspase-8 activity,and Fas and FasL levels) were similar between high-fat ApoE-/-group and high-fat ApoE-/-+ FXR antagonist group.Conclusion FXR antagonist alleviates myocardial reperfusion injury in cholesterol-fed ApoE-/-mice via inhibition of the mitochondrial-mediated and endoplasmic-reticulum stress pathway.
