中国组织工程研究

中国组织工程研究 ›› 2022, Vol. 26 ›› Issue (31): 5020-5025.doi: 10.12307/2022.721

• 干细胞基础实验 basic experiments of stem cells • 上一篇    下一篇

髓源性生长因子对小鼠老龄化左心室重构的影响

孙 迎1，向光大1，2，徐晓丽2   

  1. 1武汉科技大学研究生院，湖北省武汉市   430081；２中国人民解放军中部战区总医院内分泌科，湖北省武汉市   430070
  • 收稿日期:2021-03-25 接受日期:2021-05-12 出版日期:2022-11-08 发布日期:2022-04-25
  • 通讯作者: 向光大，博士，主任医师，中国人民解放军中部战区总医院内分泌科，湖北省武汉市 430070
  • 作者简介:孙迎，女，1993年生，湖北省孝感市人，汉族，2021年武汉科技大学毕业，硕士，主要从事内分泌与代谢病学的研究。
  • 基金资助:
    2018年度国家自然科学基金项目(81870573)，课题名称：MYDGF对糖尿病动脉粥样硬化性血管病变保护作用及机制研究，项目负责人：向光大；2015年度国家自然科学基金项目(81570730)，课题名称：GDF11对高糖状态下血管内皮细胞保护作用及机制研究，项目负责人：向光大

Effects of myeloid-derived growth factor on ventricular remodeling in aging mice

Sun Ying1, Xiang Guangda1, 2, Xu Xiaoli2   

  1. 1Graduate School of Wuhan University of Science and Technology, Wuhan 430081, Hubei Province, China; 2Department of Endocrinology, Central Theater Command General Hospital of Chinese People’s Liberation Army, Wuhan 430070, Hubei Province, China
  • Received:2021-03-25 Accepted:2021-05-12 Online:2022-11-08 Published:2022-04-25
  • Contact: Xiang Guangda, MD, Chief physician, Graduate School of Wuhan University of Science and Technology, Wuhan 430081, Hubei Province, China; Department of Endocrinology, Central Theater Command General Hospital of Chinese People’s Liberation Army, Wuhan 430070, Hubei Province, China
  • About author:Sun Ying, Master, Graduate School of Wuhan University of Science and Technology, Wuhan 430081, Hubei Province, China
  • Supported by:
    2018 National Natural Science Foundation of China, No. 81870573 (to XGD); 2015 National Natural Science Foundation of China, No. 81570730 (to XGD)

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摘要：

文题释义：
髓源性生长因子：又称MYDGF，是由19号染色体(C19orf10)上的开放阅读框编码的一种分泌蛋白。心肌梗死后，骨髓源性单核细胞和巨噬细胞内源性产生这种蛋白，以保护和修复心脏，从而促进心肌细胞的存活和血管生成。
老龄化左心室重构：随着年龄增长，老年人心脏结构、功能发生改变，其中最显著的现象是由于心肌细胞肥大而导致的左心室壁厚度增加，这种与年龄相关的左心室重构已通过纵向临床试验得到确定。

背景：增龄是众多疾病发生发展的共同危险因素，包括心血管疾病、神经退行性疾病、骨质疏松等，其中心血管疾病已经成为目前老年人死亡的主要原因之一。
目的：探讨髓源性生长因子对小鼠老龄化左心室重构的影响。
方法：普通饮食喂养C57BL/6小鼠(WT鼠)和骨髓特异性髓源性生长因子敲除小鼠(KO鼠)至15月龄大，根据是否予腺相关病毒-髓源性生长因子载体干预，随机分为以下4组：WT组、KO组、腺相关病毒-绿色荧光蛋白组、腺相关病毒-髓源性生长因子组。干预12周后，对小鼠行心脏超声检查评估其心脏结构、功能，并检测各项与心功能相关的血生化指标，称量小鼠心脏质量，同时测量其胫骨长度；苏木精-伊红、Masson染色观察心肌细胞肥大和间质纤维化程度。
结果与结论：①与WT组相比，KO组小鼠心脏质量、体质量、心脏质量/胫骨长度显著增加(P < 0.05)；②KO组小鼠左心室舒张末期内径、左心室收缩末期内径均较WT小鼠增高，左室射血分数、短轴缩短分数降低(P < 0.05)；③病理结果显示，KO组小鼠心肌细胞较WT组明显增大，且心肌纤维化程度加深；④KO组小鼠对胰岛素的敏感性降低，血糖下降比例低于WT组(P < 0.05)；血脑钠尿肽、肾素、血管紧张素Ⅱ、醛固酮及去甲肾上腺素水平较WT组增加(P < 0.05)；⑤恢复骨髓源性生长因子后上述指标均有所改善；⑥而各组小鼠间摄食量、空腹血糖、总胆固醇、三酰甘油、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇及糖化血红蛋白水平无明显区别(P > 0.05)；⑦提示髓源性生长因子缺失能够导致小鼠心肌细胞发生病理性结构改变及心功能下降，最终引起心室重构；补充髓源性生长因子后老龄化心室重构可得到一定改善，骨髓源性生长因子可能成为治疗老年小鼠心室重构的新药物。
缩略语：髓源性生长因子：myeloid-derived growth factor，MYDGF；腺相关病毒：adeno-associated viral，AAV；绿色荧光蛋白：green fluorescent protein，GFP

https://orcid.org/0000-0001-6891-3584 (孙迎) 

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 髓源性生长因子, 基因敲除, 心脏衰老, 心肌肥大, 心肌纤维化, 基因治疗, 胰岛素抵抗

Abstract: BACKGROUND: Aging is a predominant risk factor for many developing diseases, such as cardiovascular disease, neurodegenerative disease, and osteoporosis. Cardiovascular disease has become one of the main causes of death in the elderly.  
OBJECTIVE: To investigate the effect of myeloid-derived growth factor (MYDGF) on ventricular remodeling in aging mice.
METHODS:  15-month-old C57BL/6 mice (WT mice) and MYDGF-/- mice (KO mice) were randomly divided into four groups as follows: WT group, KO group, adeno-associated virus-green fluorescent protein group, and adeno-associated virus-MYDGF group according to the presence and absence of AAV MYDGF intervention. After the intervention for 12 weeks, the mice were subjected to cardiac ultrasound to evaluate their cardiac structure and function, and to detect various blood biochemical indicators related to cardiac function. The heart weight was weighed and the length of the tibia was measured. Hematoxylin-eosin staining and Masson staining were used to observe the degree of cardiomyocyte hypertrophy and interstitial fibrosis.  
RESULTS AND CONCLUSION: (1) Compared with the WT group, the heart weight, body weight, and heart weight to tibia length of KO group were increased (P < 0.05). (2) Left ventricular end-diastolic diameter and left ventricular end-systolic dimension in the KO group were enlarged compared with the WT group. Importantly, the ejection fractions and fractional shortening were decreased (P < 0.05). (3) Pathological results showed that compared with the WT group, the myocardial cells of the KO group were significantly enlarged, and the degree of myocardial fibrosis was deepened. (4) The sensitivity to insulin of the mice in the KO group decreased, and the rate of blood glucose decline was lower than that in the WT group (P < 0.05). There was a significant increase in brain natriuretic peptide, plasma renin activity, angiotensin II, aldosterone, and norepinephrine levels in the circulation of KO mice compared to WT mice (P < 0.05). (5) After treatment of MYDGF, the above indicators had been improved. (6) There was no significant difference in food intake, fasting blood glucose, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and glycosylated hemoglobin levels among the groups (P > 0.05). (7) It is indicated that the lack of MYDGF can lead to pathological structural changes and decreased cardiac function in mouse cardiomyocytes, and finally cause ventricular remodeling; aging ventricular remodeling can be improved after MYDGF replenishment. MYDGF may become a new drug for the treatment of ventricular remodeling in elderly mice.

Key words: myeloid-derived growth factor, gene knockout, heart aging, cardiac hypertrophy, myocardial fibrosis, gene therapy, insulin resistance

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