方欢乐 李晓明 倪敏黾 赵玉文 杨永华

中圖分类号 R542.2;R965 文献标志码 A 文章编号 1001-0408（2021）10-1246-06

DOI 10.6039/j.issn.1001-0408.2021.10.15

摘 要 目的：研究α7烟碱型乙酰胆碱受体激动剂PNU282987对小鼠心脏重塑的改善作用及对Janus激酶2/信号转导及转录激活因子3（JAK2/STAT3）信号通路的影响。方法：将雄性昆明种小鼠随机分为正常对照组、模型组、普萘洛尔组（阳性对照，灌胃40 mg/kg）和PNU282987低、中、高剂量组（腹腔注射0.5、1.0、3.0 mg/kg），每组10只。除正常对照组外，其余各组小鼠皮下注射异丙肾上腺素（ISO，30 mg/kg）7天以复制心脏重塑模型;各给药组小鼠均于ISO注射30 min后给予相应药液，每天1次，连续7天。末次给药12 h后，检测各组小鼠左室射血分数（EF）和左室短轴缩短率（FS），计算全心质量指数（HMI），观察其心肌组织形态学特征，测定血清中乳酸脱氢酶（LDH）、肌酸激酶（CK）、肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）含量和细胞间黏附分子1（ICAM-1）、血管细胞黏附分子1（VCAM-1）蛋白表达水平，检测心肌组织中磷酸化JAK2（p-JAK2）/JAK2、磷酸化STAT3（p-STAT3）/STAT3比值。结果：与正常对照组比较，模型组小鼠EF、FS均显著降低，HMI，LDH、CK、TNF-α、IL-6含量，ICAM-1、VCAM-1蛋白表达水平和p-JAK2/JAK2、p-STAT3/STAT3比值均显著升高（P<0.05或P<0.01），心肌间质蓝色胶原沉积明显，纤维化程度较重。与模型组比较，PNU282987中、高剂量组和普萘洛尔组小鼠EF、FS均显著升高，HMI（PNU282987中剂量组除外），LDH（PNU282987中剂量组除外）、CK、TNF-α、IL-6含量，ICAM-1、VCAM-1蛋白表达水平和p-JAK2/JAK2、p-STAT3/STAT3比值均显著降低（P<0.05或P<0.01），心肌间质蓝色胶原沉积明显减少，心肌纤维化程度明显降低;而PNU282987低剂量组小鼠上述指标变比较差异无明显变化（P>0.05）。结论：PNU282987可改善小鼠的心脏重塑，其机制可能与抑制JAK2/STAT3信号通路有关。

关键词 PNU282987;异丙肾上腺素;心脏重塑;抗炎作用;Janus激酶2/信号转导及转录激活因子3信号通路;小鼠

Effects of PNU282987 on Improving Cardiac Remodeling and JAK2/STAT3 Signaling Pathway

FANG Huanle1，LI Xiaoming1，NI Minmin1，ZHAO Yuwen1，YANG Yonghua2（1. Medical College， Xian Peihua University，Xian 710125，China; 2. Dept. of Pediatrics， the First Affiliated Hospital of Xian Jiaotong University， Xian 710061，China）

ABSTRACT   OBJECTIVE： To study the effects of α7 nicotinic acetylcholine receptor agonists （PNU282987） on improving cardiac remodeling of mice and Janus kinase 2/signal transducer and activator of transcription 3（JAK2/STAT3）signaling pathway. METHODS： Male Kunming mice were randomly divided into normal control group， model group， propranolol group （positive control， i.g. 40 mg/kg） and PNU282987 low-dose， medium-close and high-dose groups （intraperitoneal injection of 0.5， 1.0， 3.0 mg/kg）， with 10 mice in each group. Except for the normal control group， mice in the other groups were given isoproterenol （ISO， 30 mg/kg） subcutaneously for 7 days to induce the cardiac remodeling model. After 30 minutes of ISO injection， administration groups were given relevant liquid， once a day， for 7 consecutive days. Twelve hours after last administration， the left ventricular ejection fraction （EF） and left ventricular short axis shortening rate （FS） of mice in each group were measured， and the whole heart mass index （HMI） was calculated; the pathological changes of myocardium were observed. The serum contents of lactate dehydrogenase （LDH）， creatine kinase （CK）， tumor necrosis factor α （TNF-α）， interleukin 6 （IL-6）， the protein expression of intercellular adhesion molecule 1 （ICAM-1） and adhesion molecule 1 （VCAM-1） were also determined. The ratios of p-JAK2/JAK2， p-STAT3/STAT3 in myocardial tissue were detected. RESULTS： Compared with normal control group， EF and FS of model group were significantly reduced， HMI， the contents of LDH， CK， TNF-α and IL-6， the protein expression of ICAM-1 and VCAM-1， the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 were increased significantly （P<0.05 or P<0.01）; blue collagen deposition in the interstitium of myocardium was obvious， and the degree of fibrosis was severe. Compared with model group， the EF and FS of the mice in the PNU282987 medium-dose and high-dose groups were increased significantly， HMI （except for PNU282987 medium-dose group）， the contents of LDH （except for PNU282987 medium-dose group）， CK， TNF-α and IL-6， the protein expression of ICAM-1 and VCAM-1， the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 were decreased significantly （P<0.05 or P<0.01）; blue collagen deposition in the myocardial interstitium was significantly reduced， and the degree of myocardial fibrosis was significantly reduced. There was no significant difference in the comparison of the above indicators in PNU282987 low-dose group （P>0.05）. CONCLUSIONS： PNU282987 can improve cardiac remodeling of mice， the mechanism of which may be associated with inhibiting JAK2/STAT3 signaling pathway.

KEYWORDS   PNU282987; Isoproterenol; Cardiac remodeling; Anti-inflammatory effect; JAK2/STAT3 signaling pathway; Mice

常见的心血管疾病包括高血压、冠心病等，其发展为心力衰竭的重要原因是发生了心脏重塑[1]。因此，减缓或者逆转患者心脏重塑是临床治疗心血管疾病的重点[2]。心脏重塑的发生涉及心脏多种病理改变，如心脏指数增加、心肌肥厚及纤维化、心肌细胞凋亡等[3]。目前，靶向心脏重塑的治疗虽可延缓心血管疾病患者出现心力衰竭，但是在多数情况下，其病情仍在持续进展，故迫切需要寻找一种创新的治疗方法[4]。……