心力衰竭发展过程中β_3肾上腺素受体自身抗体的产生及意义

Production and pathophysiological significance of autoantibodies against β_3-adrenoceptor during progression of chronic heart failure in rats

目的为加深对心力衰竭自身免疫机制的理解,研究了在心力衰竭发生发展过程中β3肾上腺素受体(β3AR)自身抗体的产生及其意义。方法采用腹主动脉缩窄法制备心力衰竭大鼠模型,应用酶联免疫吸附试验(ELISA)方法检测大鼠血清中针对β3AR细胞外第2环的自身抗体,并观察了其生物效应。结果①实施腹主动脉缩窄术4周后,心力衰竭模型组大鼠心脏质量与体质量的比值明显增加,8周后心功能各项指标显著降低,并随时间进一步加重,光镜下显示心肌呈多灶性变性病变,发生严重胶原纤维化,胶原容积分数显著增加,表明心力衰竭模型制备成功;②心力衰竭模型大鼠血清中β3AR自身抗体水平(吸光度值)在术后4周即明显升高,至8周时达峰值,保持至12周后,该抗体水平又开始下降。这表明在心力衰竭发展过程中,机体可产生β3AR自身抗体,并呈现产生、维持和自然消退的自我消长变化规律;③β3AR自身抗体对乳鼠心肌细胞跳动频率有明显的抑制效应,该效应可被非特异性βAR拮抗剂bupranolol所阻断,但不能被特异性β1AR和β2AR拮抗剂nadolol所阻断,说明该负性变时效应主要是通过β3AR介导的。结论在心力衰竭过程中产生的β3AR自身抗体可能对心力衰竭的发展有重要的病理生理作用。

Objective To investigate the production and pathophysiological significance of autoantibodies against β3-adrenoceptor（β3AR） during progression of chronic heart failure in rats for a further understanding of autoimmune mechanisms in heart failure. Methods The heart failure rat models were established by abdominal aortic banding. Anti-β3-adrenoceptor autoantibodies in the sera of rat were detected by ELISA and the biological effects of the autoantibody were observed. Results ①The heart failure model was successfully established as evidenced by increased heart weight to body weight ratio at 4 weeks after abdominal aortic banding,impaired cardiac functions at 8 weeks later,multifocal degeneration of cardiomyocyte and severe deposition of collagen over time. ②The A value of autoantibodies to β3-adrenoceptor in the sera of heart failure model was remarkably increased after 4 weeks of treatment,peaked at 8 weeks and remained plateaued until 12 weeks post treatment,and began to decline thereafter,showing a characteristic self-growth and time-course decline pattern. ③The anti-β3AR autoantibody showed significant suppression on heart-beat frequency of cultured cardiomyocytes,which is blocked with bupranolol（a nonselective antagonist of βAR） but not with nadolol（a selective antagonist of β1 and β2AR） . This negative chronotropic effect may be primarily mediated by β3AR. Conclusion Generated anti-β3AR autoantibodies may have important pathophysiologic roles in the development of heart failure.