Dataset Information

Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis.

ABSTRACT: BACKGROUND:Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention. METHODS:Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the role of an evolutionary conserved RNA-binding protein Lin28a in pathological cardiac hypertrophy. Next-generation sequencing, RNA immunoprecipitation, and gene expression analyses were applied to identify the downstream targets of Lin28a. Epistatic analysis, metabolic assays, and flux analysis were further used to characterize the effects of Lin28a and its downstream mediator in cardiomyocyte hypertrophic growth and metabolic remodeling. RESULTS:Cardiac-specific deletion of Lin28a attenuated pressure overload-induced hypertrophic growth, cardiac dysfunction, and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA and increased its transcript level. Increasing Pck2 was sufficient to promote hypertrophic growth similar to that caused by increasing Lin28a, whereas knocking down Pck2 attenuated norepinephrine-induced cardiac hypertrophy. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted the role for Lin28a and Pck2 in promoting cardiac biosynthesis required for cell growth. CONCLUSIONS:Our study demonstrates that Lin28a promotes pathological cardiac hypertrophy and glycolytic reprograming, at least in part, by binding to and stabilizing Pck2 mRNA.

SUBMITTER: Ma H

PROVIDER: S-EPMC6443464 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis.

Ma Hong H Yu Shuo S Liu Xiaojing X Zhang Yingao Y Fakadej Thomas T Liu Ziqing Z Yin Chaoying C Shen Weining W Locasale Jason W JW Taylor Joan M JM Qian Li L Liu Jiandong J

Circulation 20190401 14

<h4>Background</h4>Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention.<h4>Methods</h4>Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the ...[more]

PMID: 30636447

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Project description:Cardiomyocyte size in the healthy heart is in part determined by the level of circulating thyroid hormone (TH). Higher levels of TH induce ventricular hypertrophy, primarily in response to an increase in hemodynamic load. Normal cardiac function is maintained in this form of hypertrophy, whereas progressive contractile dysfunction is a hallmark of pathological hypertrophy. MicroRNAs (miRNAs) are important modulators of signal-transduction pathways driving adverse remodeling. Because little is known about the involvement of miRNAs in cardiac TH action and hypertrophy, we examined the miRNA expression profile of the hypertrophied left ventricle (LV) using a mouse model of TH-induced cardiac hypertrophy. C57Bl/6J mice were rendered hypothyroid by treatment with propylthiouracil and were subsequently treated for 3?days with TH (T3) or saline. T3 treatment increased LV weight by 38% (p?<?0.05). RNA was isolated from the LV and expression of 641 mouse miRNAs was determined using Taqman Megaplex arrays. Data were analyzed using RQ-manager and DataAssist. A total of 52 T3-regulated miRNAs showing a >2-fold change (p?<?0.05) were included in Ingenuity Pathway Analysis to predict target mRNAs involved in cardiac hypertrophy. The analysis was further restricted to proteins that have been validated as key factors in hypertrophic signal transduction in mouse models of ventricular remodeling. A total of 27 mRNAs were identified as bona fide targets. The predicted regulation of 19% of these targets indicates enhancement of physiological hypertrophy, while 56% indicates suppression of pathological remodeling. Our data suggest that cardiac TH action includes a novel level of regulation in which a unique set of TH-dependent miRNAs primarily suppresses pathological hypertrophic signaling. This may be relevant for our understanding of the progression of adverse remodeling, since cardiac TH levels are known to decrease substantially in various forms of pathological hypertrophy.

Project description:BackgroundThe heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis.MethodsRNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice.ResultsWe identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis.ConclusionsThese studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.

Dataset Information

Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis.

Publications

Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis.

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