Abstract 18790: Upregulation of MicroRNA29 Family Protects From Cardiac Hypertrophy and Fibrosis Modulating DNA Methyltransferases in the Novel Animal Aging Model Nothobranchius Furzeri
Introduction and Hypothesis: The short-lived (6 months) turquoise killifish Nothobranchius furzeri (NF) is a novel and convenient model organism for aging studies in which the impact of microRNAs (miRs) in cardiovascular aging emerged clear only recently. In this system, however, the engagement of miRs in the aging-associated cardiovascular degeneration is still unknown. The present study investigates the significance of miR-29 in the heart upon NF aging.
Methods and Results: Changes in miR expression in the heart of young (5 weeks) and aged (27 weeks) NFs were assessed by RNA sequencing. This analysis identified 16 up-regulated and 18 down-regulated miRs in young vs. old animals. In the heart, members of the miR-29 family turned out among the most up-regulated. To study the functional role of mir-29 we took advantage of a most suitable model for genetic manipulation as the zebrafish. To this end, we generated a transgenic zebrafish in which miR-29 family expression was down-modulated by a specific sponge targeting miR29: Actb1:eGFPsponge-29 (ZFsponge-29). MiR-29 deficiency determined morphological and histological cardiac alterations, including hypertrophy and fibrosis. Echocardiography revealed significant reduction in the ejection fraction area of ZFsponge-29 hearts (ZFsponge-29: 16.4±6.8SD; ctr: 29.9±6.8SD). Consistently, transcriptome analysis revealed an increase of collagen genes in the heart of ZFsponge-29 compared to controls. To get insights at molecular level on the role of mir-29 in NF, cardiac fibroblasts (NF-CFs) were isolated, cultured and exposed to fibrotic stimuli. Specifically, prolonged (24 hour) hypoxia (1% O2) significantly decreased miR-29 expression. Consistently, known miR-29 targets such as collagens (Col1A1, Col1B1, Col2B, Col15A1) and DNA methyltransferases (DNMTs) increased. Of note, treatment with a DNMT1 and 3b inhibitor, RG108, reduced collagen deposition and fibrotic markers.
Conclusions: Our data suggest that up-regulation of miR-29 family might represent an endogenous mechanism aimed at preventing/reducing the age-dependent cardiac damage leading to hypertrophy and fibrosis.
Author Disclosures: F. Spallotta: None. J. Heid: None. S. Atlante: None. R. Ripa: None. C. Cencioni: None. M. Baumgart: None. G. Milano: None. A. Scopece: None. C. Kuenne: None. S. Guenther: None. G. Rossi: None. T. Braun: None. G. Pompilio: None. A.M. Zeiher: None. A. Cellerino: None. C. Gaetano: None.
- © 2016 by American Heart Association, Inc.