张苗苗?李为民?董晶妹

【摘要】目的 研究心房颤动时β3-肾上腺素能受体（β3-AR）是否通过作用于尼克酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生氧化应激。方法 建立快速心房起搏心房颤动兔模型，将40只成年家兔随机分为4组，分别为假手术组（Con组）、起搏7 d组（P7组）、β3-AR激动剂组（BRL组）和β3-AR抑制剂组（L组）。P7组、BRL组和L组在术后1周后分别给予β1-AR、β2-AR抑制剂纳多洛尔、纳多洛尔+β3-AR激动剂（BRL37344）和纳多洛尔+β3-AR抑制剂（L748337）。1周后取材，分别检测各组心房组织中超氧化物歧化酶（SOD）活力、丙二醛和NADPH氧化酶2（NOX2）含量。结果 与Con组相比，P7组心房组织SOD活力降低（P < 0.05），丙二醛、NOX2含量增加（P均< 0.05）。给予β3-AR激动剂后，BRL组SOD活力进一步降低（P < 0.05），NOX2含量增加（P < 0.05）。給予β3-AR抑制剂后，L组SOD活力较P7组增加（P < 0.05），丙二醛含量进一步降低（P < 0.05），NOX2含量亦降低（P < 0.05）。结论 家兔快速心房起搏后心房肌发生氧化应激，激动β3-AR加重氧化应激，而抑制β3-AR后可减轻氧化应激。β3-AR可能通过NADPH氧化酶途径产生氧化应激。β3-AR和NADPH氧化酶有望成为防治心房颤动的新靶点。

【关键词】心房颤动;氧化应激;β3-肾上腺素能受体;

尼克酰胺腺嘌呤二核苷酸磷酸氧化酶

Roles of β3 adrenergic receptor in oxidative stress of atrial fibrillation via NADPH oxidase pathway Zhang Miaomiao， Li Weimin， Dong Jingmei. Department of Cardiology， the First Affiliated Hospital of Harbin Medical University， Harbin 150001， China

【Abstract】Objective To explore whether β3 adrenergic receptor contributed to the oxidative stress of atrial fibrillation by NADPH oxidases in the rabbit models with rapid atrial pacing. Methods The rabbit models with rapid atrial pacing were established. Forty rabbits were randomly divided into four groups： sham operation group（Con group）， 7-d pacing group（P7 group）， β3 adrenergic receptor agonist group（BRL group）and β3 adrenergic receptor antagonist group（L group）， respectively. Nadolol， Nadolol+BRL37344 and Nadolol+L748337 were administered at postoperative 1 week in the P7， BRL and L groups， respectively. At 1 week after sample collection， superoxide dismutase （SOD），malondialdehyde （MDA） and NADPH oxidase 2 （NOX2） were quantitatively measured. Results Compared with the Con group， the SOD activity was significantly decrease， whereas MDA and NOX2 levels were remarkably increased in P7 group （all P < 0.05）. The SOD activity was significantly decreased， whereas the NOX2 level was considerably increased by β3 adrenergic receptor agonist （all P < 0.05）. After the administration of β3 adrenergic receptor agonist， the SOD activity was significantly higher， whereas the MDA and NOX2 levels in the Con group were considerably declined compared with those in the P7 group （all P < 0.05）.  Conclusions Oxidative stress occurs in the atrial muscle of rabbit models with rapid atrial pacing.β3 adrenergic receptor agonist can aggravate oxidative stress， whereas inhibition of β3 adrenergic receptor agonist can alleviate the oxidative stress. β3 adrenergic receptor can induce oxidative stress via the NADPH oxidases signaling pathway. β3 adrenergic receptor and NADPH oxidases probably become novel therapeutic targets for atrial fibrillation.

【Key words】Atrial fibrillation;Oxidative stress;β3 adrenergic receptor;

Nicotinamide vadenine dinucleotide phosphate oxidases

心房颤动是临床上最常见的心律失常之一。中国≥35岁居民的心房颤动患病率为0.71%，80岁以上心房颤动患病率达7.5%[1]。心房颤动可引起血栓形成，由此引发的脑卒中更是每年增加8.3%[2]。是致残致死的重要疾病之一，严重影响人们的生活质量和寿命。但目前心房颤动的发生、发展机制尚不明确，治疗主要集中于临床症状控制和后果干预，尚无有效的早期预防措施[3]。因此，深入研究心房颤动发生、发展机制及上游治疗新靶点是目前研究的重点及热点。

研究证实心房颤动与氧化应激相关，而心房颤动发生氧化应激的主要来源为尼克酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶，其中心肌细胞中主要表达NADPH氧化酶2（NOX2）和NOX4[4]。动物实验证实心房颤动时NADPH氧化酶激活，并与Rac1相关。临床实验同样证实，相比于窦性心律者，心房颤动患者的心房肌NADPH氧化酶活性增加，进而Rac1蛋白表达上调[5-6]。……