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Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis. Circulation 2019 Apr 02;139(14):1725-1740

Date

01/15/2019

Pubmed ID

30636447

Pubmed Central ID

PMC6443464

DOI

10.1161/CIRCULATIONAHA.118.037803

Scopus ID

2-s2.0-85064219277   20 Citations

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.

Author List

Ma H, Yu S, Liu X, Zhang Y, Fakadej T, Liu Z, Yin C, Shen W, Locasale JW, Taylor JM, Qian L, Liu J

Author

Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Energy Metabolism
Glycolysis
Hypertrophy, Left Ventricular
Mice, Knockout
Mitochondria, Heart
Myocytes, Cardiac
Phosphoenolpyruvate Carboxykinase (ATP)
Protein Binding
RNA Stability
RNA, Messenger
RNA-Binding Proteins
Rats, Sprague-Dawley
Ventricular Function, Left
Ventricular Remodeling