洛沙坦和依那普利对SHR血管平滑肌细胞凋亡的影响

Dynamically effects of losartan and enalapril on vascular smooth muscle cell apoptosis in spontaneously hypertensive rats

目的动态观察自发性高血压大鼠 (SHR)血管平滑肌细胞 (VSMC)的凋亡 ,探讨血管紧张素IIAT1 R阻滞剂洛沙坦和血管紧张素转换酶抑制剂依那普利降压治疗对SHRVSMC凋亡的影响。方法末端标记法 (TUNEL)和透射电镜技术检测细胞凋亡 ,RT PCR和免疫组化方法分别检测Bax、Bcl 2基因及其蛋白的表达。结果从 12～ 2 4周龄 ,SHRVSMC凋亡逐渐减低 ,2 4周龄时 ,凋亡指数 (APOI)低于同周龄正常血压大鼠 (WKY) (P <0 .0 5 ) ;洛沙坦和依那普利降压治疗 8和 12周 ,分别使APOI增加了36 %、5 1%和 71%、35 % (P <0 .0 5 )。随周龄增加 ,SHR胸主动脉Bax基因表达逐渐下调 ,与APOI变化趋势一致 ,依那普利治疗 12周时 ,使Bax基因表达上调 (P <0 .0 5 ) ;各实验组均未检测出Bcl 2基因的表达。依那普利和洛沙坦降压治疗可使SHR胸主动脉Bax蛋白表达上调 ,BCL 2蛋白下调。结论VSMC凋亡不足可能是血管肥厚的主要原因之一 ;洛沙坦、依那普利长期降压治疗 ,可促进血管平滑肌细胞凋亡 ,其机制可能是通过促进Bax蛋白表达和 /或抑制Bcl 2蛋白表达实现。

Objective To explore the effects of the antihypertensive therapy of losartan and enalapril on vascular smooth muscle cell(VSMC) apoptosis in spontaneously hypertensive rats (SHR) by dynamical investigation. Methods Apoptosis was identified by in situ TDT-mediated dUTP nick end labeling(TUNEL) and transmissive electron microscopy. The expression of Bax and Bcl-2 gene was detected by RT-PCR, on the other hand, their protein expression was assessed by immunohistochemistry. Results The APOI of VSMC apoptosis in SHR-C decreased gradually with the increase of their age from 12 weeks old to 24 weeks old; and at the age of 24 weeks old, it was lower than that of age-matched WKY(P< 0.05). Losartan and enalapril increased APOI by 36%,51% and 71%,35% after oral therapy for 8 weeks and 12 weeks respectively (P<0.05), but had no marked effect on it when treatment less than 4 weeks. Expression of proapoptotic gene Bax in thoracic aorta tissue of SHR-C decreased gradually from 12 weeks to 24 weeks old with the same trend as that of APOI. Upregulation of the expression of Bax gene wasnt observed by antihypertensive therapy with enalapril and losartan but enalapril increased markedly the expression of Bax gene only after 12 weeks therapy. The administration with enalapril and losartan upregulated the expression of Bax protein, but downregulated the expression of Bcl-2 protein. Conclusion The lack of VSMC apoptosis may play a very important role in vascular hypertrophy in hypertensive subjects. Both losartan and enalapril can increase VSMC apoptosis after long-term therapy, which modulation mechanism is that enalapril stimulates expression of Bax gene and its counterpart protein, and inhibits expression of Bcl-2 protein. However, losartan exerts proapoptotic effect on VSMC apoptosis mostly by inhibiting expression of Bcl-2 protein.