Abstract 17690: Thyroid Hormone-Regulated Cardiac MicroRNAs May Suppress Pathological Hypertrophic Signaling
Introduction: Normal cardiomyocyte size is in part determined by the level of thyroid hormone (T3), as illustrated by the two-fold increase in cardiac mass when hypothyroid animals are treated for several days with T3. Cardiac function is maintained in this form of physiological hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy induced by chronic overload of the heart. MicroRNAs (miRs) are important modulators of signal-transduction pathways that drive adverse remodeling. In contrast, the possible involvement of miRs in cardiac T3 action and hypertrophy has not been studied.
Hypothesis: Using an unbiased approach we tested the hypothesis that T3 regulates a distinct set of cardiac miRs involved in ventricular hypertrophy.
Methods: Twelve male C57BL/6 mice were given chow containing 0.15 % propylthiouracil for 41 days to induce hypothyroidism. Six mice were injected (IP) with 5 μg T3 in 20 μl saline at day 42, 43 and 44, with six controls receiving carrier. RNA was isolated from the left ventricle at day 45. Expression of 641 currently known mouse miRs was determined using Taqman Megaplex rodent arrays. Data were analyzed using RQ-manager and DataAssist. T3-regulated miRs showing a >2-fold change (p <0.05) were included in Ingenuity Pathway Analysis to predict mRNA targets involved in cardiac hypertrophy.
Results: T3-treatment increased LV weight by 27% (p<0.05) and mRNA expression of the T3-responsive MHCα gene normalized to HPRT by 93% (p<0.05). A total of 52 miRs were differentially regulated. Pathway analysis identified 35 proteins involved in hypertrophic signal transduction as bona fide targets. Surprisingly, 75% of these targets are components of pathways known to drive pathological remodeling, including GPCR-, ERK/MAPK- and NFAT signaling. Moreover, all these components are indicated to be down regulated by the T3-dependent miRs.
Conclusion: Our data suggest that cardiac T3 action includes a novel level of regulation in which a unique set of T3-dependent miRs suppresses pathological hypertrophic signaling. This may be relevant for our understanding of the progression of adverse remodeling, since cardiac T3-levels are now known to decrease substantially in various forms of pathological hypertrophy.
Author Disclosures: R. Janssen: None. M.J. Zuidwijk: None. D.W. Kuster: None. A. Muller: None. W.J. Paulus: None. W.S. Simonides: None.
- © 2014 by American Heart Association, Inc.