地昔帕明对兔动脉斑块细胞凋亡及内质网应激的影响

Effect of desipramine on apoptosis and endoplasmic reticulum stress in atherosclerotic plaque of rabbits

目的观察地昔帕明(DES)对动脉粥样硬化(AS)模型兔斑块内细胞凋亡及内质网应激的影响。方法腹主动脉球囊损伤及高脂饲料喂养12周建立兔AS模型,最后4周随机分为AS和AS+DES组,同时设立普通饲料喂养的正常对照(NC)组和DES组,DES剂量为4 mg·kg^(-1)·d^(-1),对照组以生理盐水代替灌胃治疗。12周末,观察各组兔血清血脂水平,UPLC法测定血浆及主动脉酸性鞘磷脂酶(ASM)和神经酰胺含量,TUNEL染色测定凋亡细胞,Western blot检测GRP78和CHOP蛋白表达。结果 DES干预对正常兔和AS模型兔的TG、TC、HDL-C、LDL-C、ox-LDL水平无明显影响,但可降低血浆和主动脉ASM、神经酰胺含量及腹主动脉斑块凋亡细胞数量,下调斑块组织的GRP78和CHOP蛋白表达。结论 DES可通过抑制ASM活性,下调神经酰胺水平,改善内质网应激,从而减少AS斑块内的细胞凋亡,缓解AS斑块形成。

Aim To investigate the effect of desipramine(DES) on apoptosis and endoplasmic reticulum stress(ERS) in atherosclerotic model of rabbits. Methods The rabbit model of atherosclerosis(AS) was established through abdominal aorta balloon injury and high fat diets for 12 weeks. They were divided into high-fat diet(HFD) group and HFD+DES group randomly. The same numbers of healthy rabbits with chow diet were divided randomly into normal control(NC) group and DES group. All interventions were given for the last 4 weeks. At the end of week 12, serum lipid was tested by conventional method. Plasma ox-LDL was measured by ELISA. Plasma and arterial acid sphingomyelinase(ASM) activity and ceramide levels were detected by UPLC analysis.Cell apoptosis in abdominal aorta was measured by TUNEL staining. Expression of GRP78 and CHOP proteins were detected by Western blot. Results On the one hand, DES had no effect on serum lipid profiles including TG,TC, HDL-C,LDL-C and ox-LDL levels compared with either healthy or atherosclerosis rabbits. On the other hand, DES inhibited ASM and ceramide levels both in plasma and aorta, and decreased apoptotic cells and proteins of GRP78 and CHOP expression in abdominal aorta. Conclusions DES attenuates AS via inhibition of ASM, down-regulating ceramide, attenuating ERS and thus reducing the apoptosis of AS plaques.