Targeting SF3A2 deacetylation promotes postinfarction cardiac pathological remodeling by reprogramming cardiomyocyte metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus Norvegicus
SUBMITTER: 
Qingxia Huang
PROVIDER: PXD069931 | iProX | Mon Oct 27 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:ObjectiveExploitation of protective metabolic pathways within injured myocardium still remains an unclarified therapeutic target in heart disease. Moreover, while the roles of altered fatty acid and glucose metabolism in the failing heart have been explored, the influence of highly dynamic and nutritionally modifiable ketone body metabolism in the regulation of myocardial substrate utilization, mitochondrial bioenergetics, reactive oxygen species (ROS) generation, and hemodynamic response to injury remains undefined.MethodsHere we use mice that lack the enzyme required for terminal oxidation of ketone bodies, succinyl-CoA:3-oxoacid CoA transferase (SCOT) to determine the role of ketone body oxidation in the myocardial injury response. Tracer delivery in ex vivo perfused hearts coupled to NMR spectroscopy, in vivo high-resolution echocardiographic quantification of cardiac hemodynamics in nutritionally and surgically modified mice, and cellular and molecular measurements of energetic and oxidative stress responses are performed.ResultsWhile germline SCOT-knockout (KO) mice die in the early postnatal period, adult mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) remarkably exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to a ketogenic diet. Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. To determine the role of ketone body oxidation in the remodeling ventricle, we induced pressure overload injury by performing transverse aortic constriction (TAC) surgery in SCOT-Heart-KO and αMHC-Cre control mice. While TAC increased left ventricular mass equally in both groups, at four weeks post-TAC, myocardial ROS abundance was increased in myocardium of SCOT-Heart-KO mice, and mitochondria and myofilaments were ultrastructurally disordered. Eight weeks post-TAC, left ventricular volume was markedly increased and ejection fraction was decreased in SCOT-Heart-KO mice, while these parameters remained normal in hearts of control animals.ConclusionsThese studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and suggest that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart.
| S-EPMC4209361 | biostudies-literature
Project description:The mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR- signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling.
2021-07-30 | GSE153364 | GEO
Project description:After reporting that mice with inducible CM-specific Wnt activation (β-catΔex3) mimic pathological remodelling condition and heart failure, we further explored the cardiac-derived extracellular vesicles (EVs). EVs analysis in vivo are challenging, therefore we used a genetic model to analyze the extracellular compartment as well as the cell composition in vivo, which provided advantageous by focusing only on the relative changes between control and transgenic cells. With an improved protocol we isolated EVs from CT and β-catΔex3 hearts. The fraction containing small EVs was confirmed by electron microscopy and nanoparticle-tracking-analysis and further characterized with EV, endoplasmic reticulum and Golgi markers as well as mass spectrometry analysis. This analysis confirmed the cardiac origin of EVs and showed 47% proteins included in Exocarta Top100 candidate with a major exosome (Exo) representation. By proteomic analysis, 391 significantly differentially enriched proteins in β-catΔex3 hearts were identified, which were significantly loaded with all seven α and β chains of the constitute 20S proteasome, molecular chaperones and co-chaperones as well as proteasome associated proteins previously described in Exo (HSPA70, HSP90AB1, CRYAB, PKACA and BAG2). CRYAB, a cardiac chaperone protein that triages misfolded proteins for proteasomal degradation or repair, was confirmed to co-localize with labelled Exo in vitro. We performed single whole cell transcriptome, followed by pairwise comparison of differential expressed gene analysis (DEG) and their functional enrichment between β-catΔex3 and CT cell clusters. This revealed that different cardiomyocytes and endothelial cell subpopulations of β-catΔex3 CM were significantly active transcriptional activity of EVs secretion and protein quality control pathways. This finding was confirmed in cardiomyocytes populations of old mice subjected to experimental pressure overload to induce hypertrophy at early and late stages of remodeling, including an acute early upregulation of exosome biogenesis processes and chaperons transcripts including CRYAB at early stages. In order to model this molecular mechanism in human cells, human induced pluripotent stem cells (IPSC)-derived cardiomyocytes were subjected to pharmacological Wnt activation, which recapitulated the increased cell cycle activation as well as exosomal markers in vitro. Our results indicate a contribution of Exo-mediated maintenance of cardiomyocytes proteostasis upon pathological remodeling. Upon stress, CRYAB and co-chaperones increase binding to damaged-sarcomeric-proteins heading towards degradation, which overload the intracellular proteasomal capacity. This may activate EV-mediated cellular extrusion of misfolded proteins as a mechanism of cellular protection. Cardiac extracellular proteosome may serve as read-out of disease progression and for monitoring cellular remodeling in vivo.
2023-03-11 | PXD031113 | Pride
Project description:Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how newly proliferated cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion and migration using live-imaging and histological approaches. We observed a close interaction between protruding cardiomyocytes and macrophages at the wound border zone, and irf8 mutant zebrafish, which largely lack macrophages, exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone and genetic deletion of mmp14b led to a decrease in 1) collagen degradation at the border zone, 2) macrophage recruitment to the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion both into the injured area and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.
2025-03-11 | GSE251856 | GEO
Project description:miR-222 overexpression leads to promotion of proliferation and hypertrophy and inhibition of apoptosis in in primary neonatal rat ventricular cardiomyocytes (NRVMs). Isolated primary neonatal rat ventricular cardiomyocytes were plated in 6 cm BD Primaria tissue culture dishes. Transfection of microRNA precursors or scramble control (0.4 μM) was carried out using Lipofectamine RNAiMAX (Invitrogen) as recommended by the manufacturer. Forty-eight hours after transfection, RNAs from cultured cells and tissues were isolated with Tryzol (Invitrogen) following the manufacturesâ?? manuals. Total RNA was harvested and submitted to the Dana-Farber Cancer Institute Molecular Diagnostics Laboratory for assay. These results revealed miR-222 regulated gene expression in primary neonatal rat ventricular cardiomyocytes. Gene expression in NRVM cells tranfected with control scramble precursor (4 samples) or miR-222 precursor (4 smaples ) was evaluated using Affymetrix Rat Genome 230 v2.0.
2016-03-03 | E-GEOD-59641 | biostudies-arrayexpress
Project description:Cardiac Remodeling During Pregnancy With Metabolic Syndrome: Prologue of Pathological Remodeling
| PRJNA993651 | ENA
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260464 | GEO
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260465 | GEO
Project description:Acute occlusion of a coronary artery results in swift tissue necrosis. Bordering areas of the infarcted myocardium may also experience impaired blood supply and reduced oxygen delivery leading to altered metabolic and mechanical processes. While transcriptional changes in hypoxic cardiomyocytes are well-studied, little is known about the proteins that are actively secreted from these cells. We established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Further functional validation experiments included ELISA measurement of human samples, murine LAD ligation and adeno-associated virus (AAV) 9-mediated in vivo overexpression in mice. The presented approach is feasible for the analysis of the secretome of primary cardiomyocytes without serum starvation. 1026 proteins were identified to be secreted within 24 hours, indicating a 5-fold increase in detection compared to former approaches. Among them, a variety of proteins have so far not been explored in the context of cardiovascular pathologies. One of the most strongly upregulated secreted factors upon hypoxia was proprotein convertase subtilisin/kexin type 6 (PCSK6). Validation experiments revealed an increase of PCSK6 on mRNA and protein level in hypoxic cardiomyocytes. PCSK6 expression was elevated in hearts of mice following 3 days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements in human serum also indicate distinct kinetics for PCSK6 in patients suffering from acute myocardial infarction, with a peak on day 3 post-infarction. Transfer of PCSK6-depleted cardiomyocyte secretome resulted in decreased expression of collagen I and III in fibroblasts compared to control treated cells, and siRNA mediated knockdown of PCSK6 in cardiomyocytes impacted transforming growth factor-β activation and mothers against decapentaplegic homolog 3 (SMAD3) translocation in fibroblasts. An Adeno-associated virus (AAV) 9-mediated, cardiomyocyte-specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis as well as decreased left ventricular function after myocardial infarction. In conclusion, a novel mass spectrometry-based approach allows the investigation of the secretome of primary cardiomyocytes. Analysis of hypoxia-induced secretion led to the identification of PCSK6 to be crucially involved in cardiac remodeling after acute myocardial infarction. Secretome analysis was performed on neonatal rat ventricular cardiomyocytes (NRVCMs) which were incubated under hypoxic conditions (1.5% O2, 5% CO2, 93.5% N2) for 12 (Hypoxia 0-12h), 24 (Hypoxia 0-24h) and 30 (Hypoxia 24-30h) hours. Furthermore, knockdown (KD) of PCSK6 in vitro mediated by small interfering RNA (siRNA) was performed to investigate changes in the secretome of cardiomyocytes with PCSK6 KD vs. control (control siRNA) during 24 hours of hypoxia (PCSK6 KD 0-24h). Cells were pulse-labeled with AHA (L-azidohomoalanine) and SILAC (stable isotope labeling with amino acids in cell culture) for 12 (Hypoxia 0-12h), 24 (Hypoxia 0-24h/PCSK6 KD 0-24h) and 6 hours (Hypoxia 24-30h). For Hypoxia 0-12h 3 replicates, Hypoxia 0-24h 6 replicates, PCSK6 KD 0-24h 3 Replicates and Hypoxia 24-30h 2 replicates were performed with label-swap.
2020-03-05 | PXD016178 | Pride
Project description:The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders. The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet–feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)–induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat). Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery. These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.
2023-07-13 | GSE237063 | GEO