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 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 The Drosophila Citrate Lyase Is Required for Cell Division during Spermatogenesis

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 206
Author(s):  
Maria Laura Di Giorgio ◽  
Patrizia Morciano ◽  
Elisabetta Bucciarelli ◽  
Antonella Porrazzo ◽  
Francesca Cipressa ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Division ◽  
Histone Acetylation ◽  
Male Meiosis ◽  
Metabolic Enzyme ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Alternative Pathways ◽  
Citrate Lyase ◽  
First Time

The Drosophila melanogaster DmATPCL gene encodes for the human ATP Citrate Lyase (ACL) ortholog, a metabolic enzyme that from citrate generates glucose-derived Acetyl-CoA, which fuels central biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine, and the acetylation of proteins and histones. We had previously reported that, although loss of Drosophila ATPCL reduced levels of Acetyl-CoA, unlike its human counterpart, it does not affect global histone acetylation and gene expression, suggesting that its role in histone acetylation is either partially redundant in Drosophila or compensated by alternative pathways. Here, we describe that depletion of DmATPCL affects spindle organization, cytokinesis, and fusome assembly during male meiosis, revealing an unanticipated role for DmATPCL during spermatogenesis. We also show that DmATPCL mutant meiotic phenotype is in part caused by a reduction of fatty acids, but not of triglycerides or cholesterol, indicating that DmATPCL-derived Acetyl-CoA is predominantly devoted to the biosynthesis of fatty acids during spermatogenesis. Collectively, our results unveil for the first time an involvement for DmATPCL in the regulation of meiotic cell division, which is likely conserved in human cells.

Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

2021 ◽  
pp. 107424842198957
Author(s):  
Yuting Tang ◽  
Xiaofang Lin ◽  
Cheng Chen ◽  
Zhongyi Tong ◽  
Hui Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Early Phase ◽  
Heart Function ◽  
Macrophage Polarization ◽  
Late Phase ◽  
Macrophage Infiltration ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization ◽  
Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

Delivery of CD151 by Ultrasound Microbubbles in Rabbit Myocardial Infarction

Cardiology ◽  
2016 ◽  
Vol 135 (4) ◽  
pp. 221-227 ◽  
Author(s):  
Shao-Ling Yang ◽  
Ke-Qiang Tang ◽  
Jun-Jia Tao ◽  
Ai-Hong Wan ◽  
Yan-Duan Lin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Function ◽  
Rabbit Model ◽  
Physiological Saline ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Therapeutic Effects ◽  
Ventricular Ejection Fraction ◽  
Cluster Of Differentiation

Objectives: We aimed to evaluate whether ultrasound (US) and microbubble-mediated delivery of Cluster of Differentiation 151 (CD151) could enhance the therapeutic effects of CD151 on myocardial infarction (MI). Methods: A rabbit model of MI was established by a modified Fujita method. Then, 50 MI rabbits were randomly divided into 5 groups, including G1 (CD151 plasmid and physiological saline in the presence of US); G2 (CD151 and Sonovue in the presence of US); G3 (CD151 and Sonovue in the absence of US); G4 (Sonovue in the absence of US), and a control group (physiological saline in the absence of US). After 14 days of treatment, the expression of CD151 was detected by Western blot. Besides, vessel density of peri-infarcted myocardium was measured by immunohistochemistry, and cardiac function was analyzed by echocardiography. Results: The rabbit model of MI was established successfully. CD151 injection increased the expression of CD151 and microvessel density in the myocardium of MI rabbits. Heart function was significantly improved by CD151, which exhibited increased left ventricular ejection fraction, left ventricular fractional shortening and a reduced Tei index. Besides, US Sonovue significantly increased the expression efficiency of CD151. Conclusion: US microbubble was an effective vector for CD151 delivery. CD151 might be an effective therapeutic target for MI.

scholarly journals Heart Repair Using Nanogel-Encapsulated Human Cardiac Stem Cells in Mice and Pigs with Myocardial Infarction

ACS Nano ◽  
2017 ◽  
Vol 11 (10) ◽  
pp. 9738-9749 ◽  
Author(s):  
Junnan Tang ◽  
Xiaolin Cui ◽  
Thomas G. Caranasos ◽  
M. Taylor Hensley ◽  
Adam C. Vandergriff ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Stem Cells ◽  
Heart Repair

Abstract 58: AT2 Receptor Agonism Regulates TIMP1/MMP9 Axis in the Heart Preventing Cardiac Fibrosis and Improving Heart Function After Experimental Myocardial Infarction

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Dilyara Lauer ◽  
Svetlana Slavic ◽  
Manuela Sommerfeld ◽  
Christa Thöne-Reineke ◽  
Yuliya Sharkovska ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricle ◽  
Late Stage ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Collagen Content ◽  
Vehicle Group ◽  
At2 Receptor ◽  
Down Regulation ◽  
Tgf Β1

Aims: A selective nonpeptide agonist for the angiotensin AT2 receptor compound 21 (C21) improved cardiac functions 7 days after myocardial infarction (MI). Here, we aimed to investigate what are the cellular mechanisms underlying cardiac protection in the late stage after MI. Methods and Results: MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.03mg/kg i.p. daily) started 6h after MI and continued for 6 weeks. Hemodynamic parameters were measured via transthoracic Doppler echocardiography and intracardiac Samba catheter. The expression of MMP9, TIMP1, TGF-β1 and collagen content were determined in left ventricle. Anti-proteolytic effects were additionally studied in primary cardiac fibroblasts. C21 significantly improved systolic and diastolic function 6 weeks after MI in comparison with the vehicle group as shown by ejection fraction (71.2±4.7 % vs. 53.4±7.0%; p<0.001), fractional shortening (40.8±2.3% vs. 30.9±3.1%; p<0.05), LVIDs (4.4±0.5mm vs. 5.2±0.8mm; p<0.05), LV EDP (16.9±1.2mmHg vs. 22.1±1.4mmHg; p<0.05), E/A ratio, dP/dt max and dP/dt min (p<0.05). Moreover, C21 improved arterial stiffness parameter (AIx) (18±1.2% vs. 25%±1.8, p<0.05) and reduced collagen content (15%; p<0.05) in postinfarcted myocardium. TIMP1 protein expression in the left ventricle was strongly up-regulated (17.7-fold; p<0.05) whereas MMP9 and TGF-β1 were significantly down-regulated (1.5-fold, p<0.05; 3.4-fold p<0.001, respectively) in the treated group. In cardiac fibroblasts, C21 primarily induced TIMP1 expression followed by attenuated MMP9 secretion and TGF-β1 down-regulation. Conclusion: C21 improves heart function in the late stage after MI and prevents cardiac remodeling. Activation of TIMP1 and subsequent inhibition of MMP9-mediated proteolysis as well as down-regulation of TGF-β1 followed by decreased collagen accumulation may attenuate disintegration of the extracellular matrix and reduce fibrosis.

Metabolism-driven post-translational modifications of H3K9 in early bovine embryos

Reproduction ◽  
2021 ◽  
Vol 162 (3) ◽  
pp. 181-191
Author(s):  
Jessica Ispada ◽  
Aldcejam Martins da Fonseca Junior ◽  
Otávio Luiz Ramos Santos ◽  
Camila Bruna de Lima ◽  
Erika Cristina dos Santos ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Developmental Stages ◽  
De Novo ◽  
Blastocyst Stage ◽  
Developmental Model ◽  
Bovine Embryos ◽  
Acetyl Coa ◽  
Post Translational Modifications ◽  
The Relationship ◽  
Different Levels

Metabolic and molecular profiles were reported as different for bovine embryos with distinct kinetics during the first cleavages. In this study, we used this same developmental model (fast vs slow) to determine if the relationship between metabolism and developmental kinetics affects the levels of acetylation or tri-methylation at histone H3 lysine 9 (H3K9ac and H3K9me3, respectively). Fast and slow developing embryos presented different levels of H3K9ac and H3K9me3 from the earliest stages of development (40 and 96 hpi) and up to the blastocyst stage. For H3K9me3, both groups of embryos presented a wave of demethylation and de novo methylation, although it was more pronounced in fast than slow embryos, resulting in blastocysts with higher levels of this mark. The H3K9ac reprogramming profile was distinct between kinetics groups. While slow embryos presented a wave of deacetylation, followed by an increase in this mark at the blastocyst stage, fast embryos reduced this mark throughout all the developmental stages studied. H3K9me3 differences corresponded to writer and eraser transcript levels, while H3K9ac patterns were explained by metabolism-related gene expression. To verify if metabolic differences could alter levels of H3K9ac, embryos were cultured with sodium-iodoacetate (IA) or dichloroacetate (DCA) to disrupt the glycolytic pathway or increase acetyl-CoA production, respectively. IA reduced H3K9ac while DCA increased H3K9ac in blastocysts. Concluding, H3K9me3 and H3K9ac patterns differ between embryos with different kinetics, the second one explained by metabolic pathways involved in acetyl-CoA production. So far, this is the first study demonstrating a relationship between metabolic differences and histone post-translational modifications in bovine embryos.

Sirtuin-dependent reversible lysine acetylation controls the activity of acetyl-Coenzyme A synthetase in Campylobacter jejuni

2021 ◽  
Author(s):  
Victoria L. Jeter ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Campylobacter Jejuni ◽  
Posttranslational Modifications ◽  
Active Site ◽  
Protein Function ◽  
Metabolic Enzyme ◽  
Lysine Acetylation ◽  
Class Iii ◽  
Acetyl Coa

Posttranslational modifications are mechanisms for rapid control of protein function used by cells from all domains of life. Acetylation of the epsilon amino group ( N ε ) of an active-site lysine of the AMP-forming acetyl-CoA synthetase (Acs) enzyme is the paradigm for the posttranslational control of the activity of metabolic enzymes. In bacteria, the alluded active-site lysine of Acs enzymes can be modified by a number of different GCN5-type N -acetyltransferases (GNATs). Acs activity is lost as a result of acetylation, and restored by deacetylation. Using a heterologous host, we show that Campylobacter jejuni NCTC11168 synthesizes enzymes that control Acs function by reversible lysine acetylation (RLA). This work validates the function of gene products encoded by the cj1537c , cj1715, and cj1050c loci, namely the AMP-forming acetate:CoA ligase ( Cj Acs), a type IV GCN5-type lysine acetyltransferase (GNAT, hereafter Cj LatA), and a NAD + -dependent (class III) sirtuin deacylase ( Cj CobB), respectively. To our knowledge, these are the first in vivo and in vitro data on C. jejuni enzymes that control the activity of Cj Acs. IMPORTANCE This work is important because it provides the experimental evidence needed to support the assignment of function to three key enzymes, two of which control the reversible posttranslational modification of an active-site lysyl residue of the central metabolic enzyme acetyl-CoA synthetase ( Cj Acs). We can now generate Campylobacter jejuni mutant strains defective in these functions, so we can establish the conditions in which this mode of regulation of Cj Acs is triggered in this bacterium. Such knowledge may provide new therapeutic strategies for the control of this pathogen.

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