Abstract 375: Acetyl-CoA Production by Specific Metabolites Promotes Cardiac Repair After Myocardial Infarction via Mediating Histone Acetylation

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Ienglam Lei ◽  
Shuo Tian ◽  
Wenbin Gao ◽  
Zhong Wang
Keyword(s):  
Myocardial Infarction ◽  
Histone Acetylation ◽  
Cardiac Repair ◽  
Acetyl Coa

scholarly journals Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ienglam Lei ◽  
Shuo Tian ◽  
Wenbin Gao ◽  
Liu Liu ◽  
Yijing Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Histone Acetylation ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Carbon Sources ◽  
Metabolic Enzyme ◽  
Acetyl Coa ◽  
Antioxidant Genes ◽  
Heart Repair ◽  
Energy Deprivation

Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

scholarly journals Acetyl-CoA production by select metabolic pathways promotes cardiac repair after myocardial infarction via mediating histone acetylation

2019 ◽  
Author(s):  
Ienglam Lei ◽  
Shuo Tian ◽  
Wenbin Gao ◽  
Liu Liu ◽  
Yijing Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Histone Acetylation ◽  
Metabolic Pathways ◽  
Heart Function ◽  
Carbon Sources ◽  
Metabolic Enzyme ◽  
Acetyl Coa ◽  
Antioxidant Genes ◽  
Heart Repair ◽  
Energy Deprivation

AbstractMyocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA significantly improved heart function in I/R rats by administration of sodium octanoate (8C). Mechanistically, 8C prevented I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes HO1, NQO1 and SOD2 and inhibited cardiomyocyte apoptosis. Furthermore, we identified that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a. Therefore, our results demonstrate that 8C dramatically improves cardiac function through metabolic acetyl-CoA-mediated histone acetylation. This study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a in stimulating histone acetylation and anti-oxidative stress gene expression to combat heart injury.

scholarly journals Local activation of cardiac stem cells for post-myocardial infarction cardiac repair

2012 ◽  
Vol 16 (11) ◽  
pp. 2549-2563 ◽  
Author(s):  
Zhuzhi Wen ◽  
Zun Mai ◽  
Haifeng Zhang ◽  
Yangxin Chen ◽  
Dengfeng Geng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Repair ◽  
Post Myocardial Infarction ◽  
Cardiac Stem Cells ◽  
Local Activation

Abstract P485: Loss Of Acta2 In Cardiac Fibroblasts Does Not Prevent The Myofibroblast Differentiation Or Affect The Cardiac Repair After Myocardial Infarction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Yuxia Li ◽  
Chaoyang Li ◽  
Qianglin Liu ◽  
Leshan Wang ◽  
Adam X Bao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibroblasts ◽  
Cardiac Repair ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Myofibroblast Differentiation ◽  
Filamentous Actin ◽  
Actin Isoforms ◽  
Cytoplasmic Actin ◽  
Cardiac Myofibroblasts

In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair in the infarcted area. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2 / SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained largely unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal survival rate after MI. Moreover, Acta2 deletion did not affect the function or overall histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2 -null cardiac myofibroblasts. It was identified that Acta2 -null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a unique compensatory increase in the transcription level of Actg2 and an increase in the protein level of sarcomeric actin isoform(s). In addition, the specific muscle actin isoforms that were upregulated in Acta2 -null cardiac myofibroblasts varied between individual cells. Moreover, the formation of stress fibers by cytoplasmic actin isoforms, especially the cytoplasmic gamma-actin, was enhanced in Acta2 -null cardiac myofibroblasts despite their unchanged RNA and protein expression. In conclusion, the deletion of Acta2 does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.

Abstract 15978: Acetyl-coa Catalysis by Atp-citrate Lyase is Essential for Myofibroblast Differentiation and Persistence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael P Lazaropoulos ◽  
Andrew A Gibb ◽  
Anh Huynh ◽  
Kathryn Wellen ◽  
John W Elrod
Keyword(s):  
Histone Acetylation ◽  
Transcriptional Activation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Metabolic Reprogramming ◽  
Myofibroblast Differentiation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Matrix Deposition ◽  
Citrate Lyase

A feature of heart failure (HF) is excessive extracellular matrix deposition and cardiac remodeling by a differentiated fibroblast population known as myofibroblasts. Identifying mechanisms of myofibroblast differentiation in cardiac fibrosis could yield novel therapeutic targets to delay or reverse HF. Recent evidence suggests that myofibroblast differentiation requires metabolic reprogramming for transcriptional activation of the myofibroblast gene program by chromatin-dependent mechanisms. We previously reported that inhibition of histone demethylation blocks myofibroblast formation, however, whether histone acetylation (e.g., H3K27ac, a prominent mark associated with gene transcription) is involved in fibroblast reprogramming remains unclear. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA and therein supplies acetyl-CoA to the nucleus, where it is used as a substrate by histone acetyltransferases (HATs). To define the role of acetyl-CoA metabolism in myofibroblast differentiation, we stimulated differentiation in mouse embryonic fibroblasts (MEFs) and adult mouse cardiac fibroblasts (ACFs) with the pro-fibrotic agonist transforming growth factor β (TGFβ) and treated cells with a pharmacological inhibitor of ACLY. ACLY inhibition decreased myofibroblast gene expression in ACF and MEFs in TGFβ-stimulated myofibroblast differentiation, in addition to decreasing the population of αSMA positive MEFs. Genetic deletion of ACLY in MEFs recapitulated the results observed with pharmacological inhibition. Encouragingly, the ACLY inhibitor was sufficient to revert fully differentiated myofibroblasts under continuous TGFβ stimulation to a quiescent, non-fibrotic phenotype. Altogether, our data indicate that ACLY activity is necessary for myofibroblast differentiation and persistence. We hypothesize that ACLY-dependent acetyl-CoA synthesis is necessary for histone acetylation and transcriptional activation of the myofibroblast gene program. Currently, we are examining mechanisms of ACLY-dependent chromatin remodeling in fibroblasts and the in vivo relevance of this mechanism in mutant mice. In summary, ACLY is a potential target to reverse cardiac fibrosis and lessen HF.

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