CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress
- 17 May 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 127 (5), 631-646
- https://doi.org/10.1161/CIRCRESAHA.119.315881
Abstract
Rationale: Cardiac CITED4 (CBP/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxylterminal domain4) is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown. Objective: To investigate the role of CITED4 in murine models of exercise and pressure overload. Methods and Results: We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, Western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA (microRNA) expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mTOR (mammalian target of rapamycin) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a profibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC. Conclusions: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.Funding Information
- Deutsche Forschungsgemeinschaft (LE 3257 1-1)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01AG061034)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL110733)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL122987)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL135886)
- HHS | NIH | National Heart, Lung, and Blood Institute (R01HL122547)
- American Heart Association (16SFRN31720000)
- HHS | NIH | National Center for Advancing Translational Sciences (UL1TR002541)
This publication has 66 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- iTRAQ Labeling is Superior to mTRAQ for Quantitative Global Proteomics and PhosphoproteomicsMolecular & Cellular Proteomics, 2012
- Quantitative Proteomics Reveals Dynamic Changes in the Plasma Membrane During Arabidopsis Immune SignalingMolecular & Cellular Proteomics, 2012
- Integrative genomics viewerNature Biotechnology, 2011
- C/EBPβ Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac RemodelingCell, 2010
- A framework for oligonucleotide microarray preprocessingBioinformatics, 2010
- Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosisProceedings of the National Academy of Sciences of the United States of America, 2008
- Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1αProceedings of the National Academy of Sciences of the United States of America, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003