Retinoic acid regulates pyruvate dehydrogenase kinase 4 (<i>Pdk4</i>) to modulate fuel utilization in the adult heart: Insights from wild‐type and β‐carotene 9′,10′ oxygenase knockout mice

Holloway, Chelsee; Zhong, Guo; Kim, Youn‐Kyung; Ye, Hong; Sampath, Harini; Hämmerling, Ulrich; Isoherranen, Nina; Quadro, Loredana

doi:10.1096/fj.202101910rr

Cited by 4 publications

(2 citation statements)

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“…HSDL2 was found to be associated with fatty acid metabolism in the present study, and indeed the silencing of HSDL2 results in the inhibition of lipid metabolism, and therefore lower availability of the principal source of energy for cardiomyocytes, the oxidation of long-chain fatty acids (36), which causes heart failure. Low BCO2 expression causes cardiac retinoic acid deficiency and impaired metabolic flexibility in mice, and this is associated with impaired activation of the PDK4/PDH pathway (37). In addition, in vitro studies have shown that BCO2 activity is 7% higher in medium containing 5 mM Cu 2+ (38), suggesting that copper ions may be involved in various pathophysiological processes in cardiomyocytes through an effect on BCO2 activity, and thereby the PDK4/PDH pathway, which affects myocardial energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis

Chen,

Yang,

et al. 2024

Front. Endocrinol.

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BackgroundDiabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients’ health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes.MaterialsCuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database.MethodsThe consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes.ResultsThere were four key genes: HSDL2, BCO2, CORIN, and SNORA80E. HSDL2, BCO2, and CORIN were negatively associated with multiple immune factors, while SNORA80E was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure.ConclusionHSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene LOXL2 is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.

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Section: Discussionmentioning

confidence: 99%

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis

Chen,

Yang,

et al. 2024

Front. Endocrinol.

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“…On the other hand, retinoids, such as fenretinide and tretinoin, have less evidence in the context of AF. However, it has been shown that these molecules can improve myocardial energy metabolism through modulation of pyruvate dehydrogenase kinase, decreasing the incidence of ventricular arrhythmias in murine models of ischemia-reperfusion [92][93][94]. The variety of compounds identified and their multiple mechanisms of action highlight the complexity of the mechanisms related to the development and perpetuation of this arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Landscape of Atrial Fibrillation: A Systematic Review and Meta-analysis

Gómez-Ochoa,

Möhn,

Malz

et al. 2023

Preprint

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Background and AimsDespite advances in understanding atrial fibrillation (AF) pathophysiology through the lens of transcriptomics, marked differences in the key AF genes between studies remain, while drugs targeting preserved dysregulated pathways are limited. This systematic review and meta-analysis aimed to provide a consensus transcriptional signature of AF and use it to identify potentially repurposable drugs.MethodsBibliographic databases and data repositories were systematically searched for studies reporting gene expression patterns in atrial heart auricle tissue from patients with AF and controls in sinus rhythm. A qualitative synthesis and a transcriptomics meta-analysis were performed. We calculated the pooled differences in individual gene expression to create a consensus signature (CS), from which we identified differentially regulated pathways and estimated transcription factors activity. We also created a protein-protein interaction network to identify drug interactions with highly interconnected genes (hub genes) from the AF-CS.ResultsThirty-four observational studies were assessed in the qualitative synthesis, while fourteen, comprising 511 samples (338 AF and 173 SR), were included in the meta-analysis. Despite the heterogeneity observed across individual studies, the AF-CS in both chambers were consistent and robust, showing a better performance in classifying AF status than individual studies. The functional analysis revealed commonality in the dysregulated cellular processes across the atria, including extracellular matrix remodeling, downregulation of cardiac conduction pathways, metabolic derangements, and innate immune system activity processes. Finally, drug-gene analyses highlighted several compounds as repurposing drug candidates for AF, highlighting lipid-lowering agents, antioxidants, and retinoids, among others.ConclusionsDespite variability in individual studies, this meta-analysis elucidated conserved molecular pathways involved in AF pathophysiology across its phenotypes, offering robust and potentially generalizable diagnostic biomarkers. From this AF-CS, we identified potential compounds targeting these dysregulated pathways, thereby addressing an extant gap in AF-specific pharmacotherapy.Key QuestionCan a meta-analytically derived consensus transcriptional signature effectively capture the core molecular mechanisms underlying AF and serve as a basis for identifying novel drug candidates targeting these conserved pathways?Key FindingsExtracellular matrix remodeling, downregulation of cardiac conduction pathways, and modulation of innate immune system activity emerged as conserved molecular hallmarks across the AF spectrum. Drug-gene interaction analyses highlighted the repurposing potential of lipid-lowering agents, antioxidants, and retinoids, among other compounds, for targeted intervention in these dysregulated pathways.Take Home MessageDespite AF’s complexity, a transcriptional signature derived through a meta-analysis can pinpoint conserved molecular pathways across AF phenotypes. These insights provide a foundation for identifying and repurposing drugs targeting the core dysregulated processes in the disease, offering new avenues for targeted, mechanism-based treatment of AF.GRAPHICAL ABSTRACT

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The microbiome as a major function of the gastrointestinal tract and its implication in micronutrient metabolism and chronic diseases

Lin

Medeiros

2023

Nutrition Research

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Retinoic acid regulates pyruvate dehydrogenase kinase 4 (Pdk4) to modulate fuel utilization in the adult heart: Insights from wild‐type and β‐carotene 9′,10′ oxygenase knockout mice

Cited by 4 publications

References 103 publications

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis

The Transcriptional Landscape of Atrial Fibrillation: A Systematic Review and Meta-analysis

The microbiome as a major function of the gastrointestinal tract and its implication in micronutrient metabolism and chronic diseases

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