上海交通大学学报（医学版）2025，Vol.45Issue(8)：949-956,8.DOI:10.3969/j.issn.1674-8115.2025.08.002
端粒酶基因治疗对压力超负荷心力衰竭小鼠的影响
Effects of telomerase gene therapy on pressure overload-induced heart failure in mice
摘要
Abstract
Objective·To investigate the therapeutic effect of telomerase gene therapy(JV001)on heart failure induced by transverse aortic constriction(TAC)in mice.Methods·Male C57BL/6J mice were randomly divided into sham operation group(Sham group),model group(TAC group),and JV001 treatment group(TAC+JV001 group).An adeno-associated virus 9(AAV9)vector containing the catalytic inactivation(D868A)and nuclear export phosphorylation(Y707F)mutations in the human telomerase reverse transcriptase(hTERT)gene(AAV9-modhTERT,named JV001)was intravenously administered to TAC animals at a single dose of 4×1012 gc/kg.The Sham group and the TAC group received equivalent volumes of saline via tail vein injection.Six weeks after administration,the expression of JV001 in the heart was determined by real-time quantitative PCR(RT-qPCR).Murine cardiac functions were assessed using echocardiography.Physiological indexes of mice were recorded for calculating heart weight/body weight ratio(HW/BW)and heart weight/tibial length ratio(HW/TL).Cardiac hypertrophy was assessed using hematoxylin-eosin(HE)staining and wheat germ agglutinin(WGA)staining.Cardiac collagen deposition was observed by Masson staining.The expressions of myocardial hypertrophy-related genes(Nppa,Nppb,Myh7,Myh6)and myocardial fibrosis-related genes(Col1a1,Col3a1,Ctgf)were detected by RT-qPCR.Results·High levels of modhTERT mRNA were expressed in the hearts of mice at 6 weeks post-injection.Compared with sham-operated mice,TAC mice exhibited significantly reduced left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS).Compared to TAC mice,TAC+JV001 mice exhibited a significant improvement in LVEF and LVFS.Concurrently,there was a downregulation in the HW/BW and HW/TL in TAC+JV001 mice compared to TAC mice.Furthermore,JV001 treatment reduced the mean cardiomyocyte cross-sectional area and improved the expression levels of myocardial hypertrophy-related genes,including Nppa,Nppb,Myh7 and Myh6.Additionally,JV001 treatment ameliorated the TAC-induced increase in myocardial interstitial fibrosis and reduced the elevated expression levels of myocardial fibrosis-related genes,including Col1a1,Col3a1,and Ctgf.Conclusion·AAV9-modhTERT treatment can alleviate TAC-induced cardiac dysfunction,cardiac hypertrophy,and fibrosis in mice.关键词
心力衰竭/心肌纤维化/腺相关病毒/基因治疗/端粒酶Key words
heart failure/cardiac fibrosis/adeno-associated virus(AAV)/gene therapy/telomerase分类
医药卫生引用本文复制引用
何苏荟,赵银龙,张家毓..端粒酶基因治疗对压力超负荷心力衰竭小鼠的影响[J].上海交通大学学报（医学版）,2025,45(8):949-956,8.基金项目
国家自然科学基金(82070248,82300282) （82070248,82300282）
上海高校特聘教授(东方学者)岗位计划(0900000024). National Natural Science Foundation of China(82070248,82300282) （东方学者）
The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(0900000024). （Eastern Scholar）
