Effects of telomerase gene therapy on pressure overload-induced heart failure in mice
10.3969/j.issn.1674-8115.2025.08.002
- VernacularTitle:端粒酶基因治疗对压力超负荷心力衰竭小鼠的影响
- Author:
Suhui HE
1
;
Yinlong ZHAO
1
Author Information
1. 上海交通大学医学院附属第九人民医院上海精准医学研究院,上海 200011
- Collective Name:CHANG Alex Chia Yu
- Publication Type:Journal Article
- Keywords:
heart failure;
cardiac fibrosis;
adeno-associated virus(AAV);
gene therapy;
telomerase
- From:
Journal of Shanghai Jiaotong University(Medical Science)
2025;45(8):949-956
- CountryChina
- Language:Chinese
-
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.
