Effects of telomerase gene therapy on pressure overload-induced heart failure in mice

doi:10.3969/j.issn.1674-8115.2025.08.002

Abstract

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.

Key words: heart failure, cardiac fibrosis, adeno-associated virus (AAV), gene therapy, telomerase

CLC Number:

R541

HE Suhui, ZHAO Yinlong, CHANG Alex Chia Yu. Effects of telomerase gene therapy on pressure overload-induced heart failure in mice[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(8): 949-956.

Figures/Tables 5

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References 28

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Species	Gene	Forward primer sequence (5′→3′)	Reverse primer sequence (5′→3′)
Mus musculus	Nppa	TTCGGGGGTAGGATTGACAG	CACACCACAAGGGCTTAGGA
Mus musculus	Nppb	AGTCCTTCGGTCTCAAGGCA	CCGATCCGGTCTATCTTGTGC
Mus musculus	Myh7	ACTGTCAACACTAAGAGGGTCA	TTGGATGATTTGATCTTCCAGGG
Mus musculus	Myh6	GCCCAGTACCTCCGAAAGTC	GCCTTAACATACTCCTCCTTGTC
Mus musculus	Col1a1	TGGTACATCAGCCCGAAC	GTCAGCTGGATAGCGACA
Mus musculus	Col3a1	CTGTAACATGGAAACTGGGGAAA	CCATAGCTGAACTGAAAACCACC
Mus musculus	Ctgf	GACCCAACTATGATGCGAGCC	CCCATCCCACAGGTCTTAGAAC
Mus musculus	Gapdh	CATCACTGCCACCCAGAAGACTG	ATGCCAGTGAGCTTCCCGTTCAG
Homo sapiens	TERT	GCGGAAGACAGTGGTGAACT	TTCAGGATGGAGTAGCAGAGG

Species	Gene	Forward primer sequence (5′→3′)	Reverse primer sequence (5′→3′)
Mus musculus	Nppa	TTCGGGGGTAGGATTGACAG	CACACCACAAGGGCTTAGGA
Mus musculus	Nppb	AGTCCTTCGGTCTCAAGGCA	CCGATCCGGTCTATCTTGTGC
Mus musculus	Myh7	ACTGTCAACACTAAGAGGGTCA	TTGGATGATTTGATCTTCCAGGG
Mus musculus	Myh6	GCCCAGTACCTCCGAAAGTC	GCCTTAACATACTCCTCCTTGTC
Mus musculus	Col1a1	TGGTACATCAGCCCGAAC	GTCAGCTGGATAGCGACA
Mus musculus	Col3a1	CTGTAACATGGAAACTGGGGAAA	CCATAGCTGAACTGAAAACCACC
Mus musculus	Ctgf	GACCCAACTATGATGCGAGCC	CCCATCCCACAGGTCTTAGAAC
Mus musculus	Gapdh	CATCACTGCCACCCAGAAGACTG	ATGCCAGTGAGCTTCCCGTTCAG
Homo sapiens	TERT	GCGGAAGACAGTGGTGAACT	TTCAGGATGGAGTAGCAGAGG