高表达SEL1L减轻小鼠主动脉弓缩窄所致心脏结构和功能损伤的机制研究

李泽霖; 周海佳; 纪兆乐; 杨竞霄; 郭华; 王芳芳

doi:10.12125/j.chj.202210027

高表达SEL1L减轻小鼠主动脉弓缩窄所致心脏结构和功能损伤的机制研究

Mechanism of over-expression of SEL1L in alleviating cardiac structural and functional damage caused by transverse aortic constriction in mice

摘要

摘要:
目的内质网应激在压力过载所致心肌损伤中扮演重要作用，Lin-12样抑制子/增强子（suppressor/enhancer of Lin12-like, SEL1L）是维持内质网稳态的关键分子，本研究旨在观察高表达SEL1L对小鼠主动脉弓缩窄（transverse aortic constriction, TAC）所致心脏结构和功能损伤的影响及其可能的作用机制。
方法采用主动脉弓缩窄术建立小鼠心肌肥厚模型。40只雄性C57BL/6小鼠随机均分为4组：Sham组、主动脉弓缩窄组（TAC组）、主动脉弓缩窄+AAV9空白干预组（TAC+AAV9-Ctrl组）和主动脉弓缩窄+AAV9-SEL1L组（TAC+AAV9-SEL1L组）。TAC+AAV9-Ctrl组和TAC+AAV9-SEL1L组小鼠心肌内点注射10¹¹个单位的AAV9-Ctrl和AAV9-SEL1L病毒颗粒4周后，进行TAC手术。检测各组小鼠心脏功能，明确心肌肥厚、心肌纤维化及心肌细胞凋亡情况，同时观察心肌组织内质网应激和氧化应激水平。
结果与Sham组相比，TAC组小鼠心脏SEL1L mRNA及蛋白表达显著降低，心脏功能明显受损，心肌细胞及心脏明显肥大，心肌间质纤维化明显加重，心肌细胞凋亡显著增加，并且心肌组织内质网应激及氧化应激水平明显上调（均P<0.05）。与TAC组相比，TAC+AAV9-SEL1L组小鼠心脏SEL1L mRNA及蛋白表达显著增加，心脏功能明显改善，心肌细胞及心脏肥厚明显缓解，心肌间质纤维化程度明显减轻，心肌细胞凋亡显著被抑制，并且心肌组织内质网应激及氧化应激水平明显下调（均P<0.05）。与TAC组相比，TAC+AAV9-Ctrl组小鼠上述指标的差异无统计学意义。
结论高表达SEL1L可通过抑制心肌组织内质网应激和氧化应激，发挥减轻主动脉弓缩窄所致小鼠心脏结构和功能损伤的保护作用。

Abstract:
AIM To investigate the effect of over-expression of suppressor/enhancer of Lin12-like (SEL1L) on cardiac structural and functional damage caused by transverse aortic constriction (TAC) and its underlying mechanism.
METHODS Myocardial hypertrophy model was established by TAC operation. Forty male C57BL/6 mice were randomly divided into 4 groups: Sham group, TAC group, TAC+AAV9-Ctrl group and TAC+AAV9-SEL1L group. Mice in TAC+AAV9-Ctrl group and TAC+AAV9-SEL1L group underwent TAC surgery 4 weeks after intramuscular spot injection of 10¹¹ units of AAV9-Ctrl and AAV9-SEL1L virus particles. Cardiac functions were detected, myocardial hypertrophy, myocardial fibrosis and myocardial apoptosis were determined, and myocardial endoplasmic reticulum stress and oxidative stress were observed.
RESULTS Compared with those in Sham group, mRNA and protein expressions of SEL1L in TAC group were significantly decreased, cardiac functions were significantly impaired, cardiomyocytes and heart were significantly enlarged, myocardial fibrosis was significantly aggravated, and cardiomyocyte apoptosis was significantly increased. Besides, the levels of endoplasmic reticulum stress and oxidative stress were significantly up-regulated in TAC group (all P<0.05). Compared with those in TAC group, mRNA and protein expressions of SEL1L in TAC+AAV9-SEL1L group were significantly increased, cardiac functions were significantly improved, cardiomyocytes and cardiac hypertrophy were significantly alleviated, myocardial fibrosis was significantly mitigated, and cardiomyocyte apoptosis was significantly inhibited. Additionally, the levels of endoplasmic reticulum stress and oxidative stress were significantly down-regulated in TAC+AAV9-SEL1L group (all P<0.05). But the above indexes in TAC+AAV9-Ctrl group had no significant difference compared with those in TAC group.
CONCLUSION Over-expression of SEL1L reduces cardiac structural and functional damage caused by transverse aortic constriction in mice through inhibiting endoplasmic reticulum stress and oxidative stress.

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