FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3108323277> ?p ?o ?g. }

• W3108323277 abstract "Abstract Introduction Familial hypertrophic cardiomyopathy (HCM) is caused by over 400 mutations affecting mostly key sarcomere components, such as titin and myosin. However, HCM also results from mutations in non-structural genes such as PRKAG2 which is involved directly in a variety of bioenergetic and metabolic pathways. When the metabolic processes fail to work properly or effectively, structural and functional aberrations resulting in cardiac dysfunction can occur. Thus, mutations in the human PRKAG2 gene lead to HCM, autosomal dominant ventricular pre-excitation - Wolff-Parkinson-White syndrome (WPW), a progressive conduction system disease and vacuolar glycogen accumulation in cardiomyocytes. Purpose To investigate the hypothesis that intervening with the bioenergetic and metabolic consequences of the R302Q mutation in the PRKAG2 gene causing inherited cardiomyopathy, will attenuate the cardiac impairments. Methods We generated mutated and isogenic induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) from a WPW patient carrying the R302Q mutation. As additional control, we used healthy volunteers' iPSC-CMs. Bioenergetic (Oxygen Consumption Rate, OCR) and metabolic status were measured using the Seahorse Flux Analyzer and LC-MS, respectively. To decipher the molecular basis underlying the bioenergetic and metabolic deficits, RNA-seq analysis was performed. Results The OCR results demonstrated in PRKAG2-mutated compared to isogenic and healthy iPSC-CMs, a 2-fold increase in maximal respiration rate and a 3.75-fold increase in spare respiratory capacity, while basal OCR parameters were similar in all groups. Importantly, when treated with the AMPK activator metformin (2.5 [mM]), all the abovementioned OCR parameters were similar in the three groups. RNA-seq analysis demonstrated that of the 553 differently expressed genes (DEGs), and of the 99 DEGs mutually differentially expressed, compared to isogenic and healthy cells, the most relevant altered pathways were glycolysis, carbon metabolism, biosynthesis of amino acids, HIF-1 signaling and fructose and mannose metabolism. These findings are consistent with the LC-MS results demonstrating in PRKAG2-mutated versus isogenic and healthy iPSC-CMs, at least a 3-fold decrease in metabolites linked to the abovementioned pathways: butyryl-carnitine, creatine, docosahexaenoic acid, GMP, IMP, myristoyl-carnitine, palmitoyl-carnitine, succinyl-Cys, UMP, UTP, UDP-GlcNAc. Conclusion PRKAG2-mutated iPSC-CMs exhibit bioenergetic and metabolic aberrations, which contribute to the cardiac pathological aspects of WPW syndrome. Importantly, treatment with the AMPK activator metformin eliminated the bioenergetic abnormalities in the mutated cells, while isogenic and healthy control cells remained unaffected. Based on these novel findings, a new therapeutic modality in WPW patients may be considered. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Israel Science Foundation (ISF)" @default.
• W3108323277 created "2020-12-07" @default.
• W3108323277 creator A5020537575 @default.
• W3108323277 creator A5030529097 @default.
• W3108323277 creator A5040362363 @default.
• W3108323277 creator A5060350240 @default.
• W3108323277 creator A5066774196 @default.
• W3108323277 creator A5072631338 @default.
• W3108323277 creator A5074416601 @default.
• W3108323277 creator A5075655592 @default.
• W3108323277 creator A5078268438 @default.
• W3108323277 creator A5081750402 @default.
• W3108323277 creator A5091741754 @default.
• W3108323277 date "2020-11-01" @default.
• W3108323277 modified "2023-10-17" @default.
• W3108323277 title "Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from PRKAG2-mutated, WPW patient" @default.
• W3108323277 doi "https://doi.org/10.1093/ehjci/ehaa946.3708" @default.
• W3108323277 hasPublicationYear "2020" @default.
• W3108323277 type Work @default.
• W3108323277 sameAs 3108323277 @default.
• W3108323277 citedByCount "0" @default.
• W3108323277 crossrefType "journal-article" @default.
• W3108323277 hasAuthorship W3108323277A5020537575 @default.
• W3108323277 hasAuthorship W3108323277A5030529097 @default.
• W3108323277 hasAuthorship W3108323277A5040362363 @default.
• W3108323277 hasAuthorship W3108323277A5060350240 @default.
• W3108323277 hasAuthorship W3108323277A5066774196 @default.
• W3108323277 hasAuthorship W3108323277A5072631338 @default.
• W3108323277 hasAuthorship W3108323277A5074416601 @default.
• W3108323277 hasAuthorship W3108323277A5075655592 @default.
• W3108323277 hasAuthorship W3108323277A5078268438 @default.
• W3108323277 hasAuthorship W3108323277A5081750402 @default.
• W3108323277 hasAuthorship W3108323277A5091741754 @default.
• W3108323277 hasConcept C100206155 @default.
• W3108323277 hasConcept C104317684 @default.
• W3108323277 hasConcept C107459253 @default.
• W3108323277 hasConcept C126322002 @default.
• W3108323277 hasConcept C145103041 @default.
• W3108323277 hasConcept C2778198053 @default.
• W3108323277 hasConcept C2778797674 @default.
• W3108323277 hasConcept C28859421 @default.
• W3108323277 hasConcept C54355233 @default.
• W3108323277 hasConcept C71924100 @default.
• W3108323277 hasConcept C86803240 @default.
• W3108323277 hasConcept C95444343 @default.
• W3108323277 hasConceptScore W3108323277C100206155 @default.
• W3108323277 hasConceptScore W3108323277C104317684 @default.
• W3108323277 hasConceptScore W3108323277C107459253 @default.
• W3108323277 hasConceptScore W3108323277C126322002 @default.
• W3108323277 hasConceptScore W3108323277C145103041 @default.
• W3108323277 hasConceptScore W3108323277C2778198053 @default.
• W3108323277 hasConceptScore W3108323277C2778797674 @default.
• W3108323277 hasConceptScore W3108323277C28859421 @default.
• W3108323277 hasConceptScore W3108323277C54355233 @default.
• W3108323277 hasConceptScore W3108323277C71924100 @default.
• W3108323277 hasConceptScore W3108323277C86803240 @default.
• W3108323277 hasConceptScore W3108323277C95444343 @default.
• W3108323277 hasLocation W31083232771 @default.
• W3108323277 hasOpenAccess W3108323277 @default.
• W3108323277 hasPrimaryLocation W31083232771 @default.
• W3108323277 hasRelatedWork W8110101 @default.
• W3108323277 hasRelatedWork W9737745 @default.
• W3108323277 hasRelatedWork W10363677 @default.
• W3108323277 hasRelatedWork W11365850 @default.
• W3108323277 hasRelatedWork W14970482 @default.
• W3108323277 hasRelatedWork W16484658 @default.
• W3108323277 hasRelatedWork W17276133 @default.
• W3108323277 hasRelatedWork W1936334 @default.
• W3108323277 hasRelatedWork W2425014 @default.
• W3108323277 hasRelatedWork W8511813 @default.
• W3108323277 isParatext "false" @default.
• W3108323277 isRetracted "false" @default.
• W3108323277 magId "3108323277" @default.
• W3108323277 workType "article" @default.