髓源性生长因子对小鼠老龄化左心室重构的影响

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

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。

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.