烟酰胺单核苷酸对血管紧张素Ⅱ致小鼠心肌纤维化的抑制作用及其机制

Inhibitive effect of nicotinamide mononucleotide on angiotensin Ⅱ-induced cardiac fibrosis in mice and its mechanism

摘要:

目的 观察烟酰胺单核苷酸(NMN)对心肌纤维化小鼠的治疗作用及其机制。方法 通过皮下植入Alzet 1004微量泵泵入[1.6mg/(kg·d)]血管紧张素Ⅱ(Ang Ⅱ)构建心肌纤维化小鼠模型,对照组泵入等量的生理盐水。根据是否腹腔注射NMN分为模型组,对照组,对照+NMN组和模型+NMN组,每组各10只小鼠。观察小鼠超声心动图、血压、心脏苏木精-伊红(HE)染色以及Masson染色的变化,并采用实时定量聚合酶链式反应(RT-qPCR)及Western blot分析法观察小鼠心肌纤维化相关蛋白或基因的表达。结果 与对照组相比,模型组小鼠的心功能显著减低、心肌纤维化加重,而给与NMN治疗后,小鼠心脏射血分数改善,同时心肌纤维化程度减轻；Ang Ⅱ干预后小鼠心肌的SIRT6表达显著下降,给与NMN后,SIRT6表达上调。结论 NMN可抑制Ang Ⅱ导致的小鼠心肌纤维化,其作用可能与NMN上调SIRT6表达量相关。

Abstract:

Objective To investigate the effect of nicotinamide mononucleotide (NMN) in treatment of cardiac fibrosis in mice and the underlying mechanism. Methods A total of 40 male C57/BL6J mice (8 weeks old) were randomly divided into cardiac fibrosis model group (model group), normal control+normal saline group (control group), model+NMN group and normal control+NMN group, with 10 mice in each group. Mouse model of cardiac fibrosis was established by peritoneal injection of 1.6mg/(kg·d) angiotension Ⅱ (Ang Ⅱ) through subcutaneously implanted Alzet 1004 micropump, and the mice of the control group was pumped with the same amount of normal saline. The changes of echocardiography, blood pressure, cardiac HE staining and Masson staining were observed, and the expression of cardiac fibrosis related genes and proteins in mice were detected by real-time quantitative PCR and Western blot analysis. Results Compared with the control group, the mice in the model group had declined cardiac function and severer cardiac fibrosis, while NMN treatment improved the ejection fraction and attenuated myocardial fibrosis. The expression of SIRT6 was significantly decreased in the model group, and NMN administration up-regulated the expression of the molecule. Conclusion NMN can inhibit the cardiac fibrosis induced by Ang Ⅱ in mice, which may be associated with its up-regulation of SIRT6 expression.