C/EBPβ Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac Remodeling

Boström, Pontus; Mann, Nina; Wu, Jun; Quintero, Pablo; Plovie, Eva; Panàkovà, Daniela; Gupta, Rana K.; Xiao, Chunyang; MacRae, Calum A.; Rosenzweig, Anthony; Spiegelman, Bruce M.

doi:10.1016/j.cell.2010.11.036

Cited by 370 publications

(464 citation statements)

References 27 publications

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“…Knockdown of Chp3 expression results in cardiomyocyte hypertrophy, increased expression of the pathological hypertrophy marker atrial natriuretic factor (the single pathological marker observed to be significantly increased in the short Acsl1 ablation model), and elevated GSK3α phosphorylation, suggesting that CHP3 functions as a negative regulator of hypertrophy via inhibition of GSK3α/β phosphorylation and subsequent activation 39. In addition, the cAMP response element–binding protein (CREB) transcriptional activator, C/EBP, is thought to play a role in physiological cardiac growth and protect against pathological hypertrophy 40. Decreased CREB function is associated with pathological hypertrophy, whereas reactivation by C/EBP stabilizes adaptive hypertrophy 41.…”

Section: Discussionmentioning

confidence: 99%

Modeling the Transition From Decompensated to Pathological Hypertrophy

Pascual

Schisler

Grevengoed

et al. 2018

JAHA

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BackgroundLong‐chain acyl‐CoA synthetases (ACSL) catalyze the conversion of long‐chain fatty acids to fatty acyl‐CoAs. Cardiac‐specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1‐mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function.Methods and ResultsGlobal cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H−/− hearts 2 weeks after Acsl1 ablation. Comparison of the 2‐ and 10‐week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint.ConclusionsShort‐term cardiac‐specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart‐specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Modeling the Transition From Decompensated to Pathological Hypertrophy

Pascual

Schisler

Grevengoed

et al. 2018

JAHA

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“…Studies in animal models have linked several master TFs (Gata4, c-Myc, Nfat3, NF-κB) to the induction of pathological gene sets that leads to the development of HF (14,(29)(30)(31). Moreover, physical exercise also highly influences cardiac function through increases in expression of these specific gene sets (32). Based on these findings, we envision a rheostat-like role for p53 whereby environmental cues induce small, but highly significant, changes in the p53/Mdm2 circuitry that are transformed to broad, pleiotropic output signals that maintain the overall temporal stability of cardiac performance (Fig.…”

Section: Discussionmentioning

confidence: 99%

p53 regulates the cardiac transcriptome

Mak

Hauck

Grothe

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.

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“…8 In brief, the swimming-trained mice were subjected to a 90-minute swimming exercise session, twice a day, 5 days a week for 4 weeks. Water temperature was controlled at 30°C to 32°C.…”

Section: Swimming Exercise-induced Physiological Cardiac Hypertrophymentioning

confidence: 99%

Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

et al. 2013

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Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II–induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II–induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload–induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.

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C/EBPβ Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac Remodeling

Cited by 370 publications

References 27 publications

Modeling the Transition From Decompensated to Pathological Hypertrophy

Modeling the Transition From Decompensated to Pathological Hypertrophy

p53 regulates the cardiac transcriptome

Bone Morphogenetic Protein-4 Mediates Cardiac Hypertrophy, Apoptosis, and Fibrosis in Experimentally Pathological Cardiac Hypertrophy

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