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:Rationale: With a prevalence of 1 in 200 individuals, hypertrophic cardiomyopathy (HCM) is thought to be the most common genetic cardiac disease, with potential outcomes that include severe hypertrophy, heart failure, and sudden cardiac death (SCD). Though much research has furthered our understanding of how HCM-causing mutations in genes such as cardiac myosin-binding protein C (MYBPC3) impair contractile function, it remains unclear how such dysfunction leads to hypertrophy and/or arrhythmias, which comprise the HCM phenotype. Identification of early response mediators could provide rational therapeutic targets to reduce disease severity. Our goal was to differentiate physiologic and pathophysiologic hypertrophic growth responses and identify early genetic mediators in the development of cardiomegaly in the cardiac myosin-binding protein C-null (cMyBP-C-/-) mouse model of HCM. Methods and Results: We performed microarray analysis on left ventricles of wild-type (WT) and cMyBPC-/- mice (n = 7 each) at postnatal day (PND) 1 and PND 9, before and after the appearance of an overt HCM phenotype. Applying the criteria of ?2-fold change, we identified genes whose change was exclusive to pathophysiologic growth (n = 61), physiologic growth (n = 30), and genes whose expression changed ?2-fold in both WT and cMyBP-C-/- hearts (n = 130). Furthermore, we identified genes that were dysregulated in PND1 cMyBP-C-/- hearts prior to hypertrophy, including genes in mechanosensing pathways and potassium channels linked to arrhythmias. One gene of interest, Xirp2, and its protein product, are regulated during growth but also show early, robust prehypertrophic upregulation in cMyBP-C-/- hearts. Additionally, the transcription factor Zbtb16 also shows prehypertrophic upregulation at both gene and protein levels. Conclusion: Our transcriptome analysis generated a comprehensive data set comparing physiologic vs. hypertrophic growth in mice lacking cMyBP-C. It highlights the importance of extracellular matrix pathways in hypertrophic growth and early dysregulation of potassium channels. Prehypertrophic upregulation of Xirp2 in cMyBP-C-/- hearts supports a growing body of evidence suggesting Xirp2 has the capacity to elicit both hypertrophy and arrhythmias in HCM. Dysregulation of Xirp2, as well as Zbtb16, along with other genes associated with mechanosensing regions of the cardiomyocyte implicate stress-sensing in these regions as a potentially important early response in HCM.

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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