Non-telomeric function deficiency of TERT enhances pressure overload-induced mouse cardiac remodeling by activation of CNBP-mediated THBS3/ITGB1 pathway.

Abstract

Recent studies show that telomerase reverse transcriptase (TERT) possesses important new biological functions in gene transcription regulation, signal transduction, tumorigenesis, vascular development and mitochondrial DNA protection independent of the maintenance of telomere length. In this study we investigated the role and mechanisms of TERT in regulating the gene expression and signal transduction during pressure overload-induced cardiac remodeling. The first-generation TERT knockout (Tert-/-) and wild-type littermate control (Tert+/+) male mice were subjected to transverse aortic constriction (TAC) surgery to establish a pressure overload-induced cardiac remodeling model. We showed that pressure overload significantly increased TERT expression in the hearts at 8 weeks after TAC, whereas TERT deficiency remarkably exacerbated pressure overload-induced cardiac dysfunction, cardiac hypertrophy and fibrosis, and reduced the survival rate of the mice. In contrast, TERT overexpression reversed phenylephrine (PE)-stimulated cardiomyocyte hypertrophy and fibrosis in neonatal rat ventricular myocytes (NRVMs). Ttranscriptomic and proteomic analyses revealed that extracellular matrix (ECM)-receptor interaction was a key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway regulated by TERT in hemodynamic overload-induced cardiac remodeling. TERT knockdown greatly enhanced, while TERT overexpression inhibited the activation of the THBS3/ITGB1 signaling pathway, in which transcription factor cellular nucleic acid-binding protein (CNBP) played a pivotal mediating role by interacting with TERT. In conclusion, the non-telomeric function of TERT in gene transcription regulation and signaling transduction plays an important role during pressure overload-induced myocardial remodeling via modulating CNBP-mediated THBS3/ITGB1 signaling pathway, which provides new targets and strategies for the prevention and treatment of pressure overload-induced cardiac remodeling.