AICAR-cardioprotection in doxorubicin-induced heart failure in rats
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ABSTRACT:
PROVIDER: PRJNA903484 | ENA |
REPOSITORIES: ENA
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Project description:Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. This was associated with normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number. In addition, we found that AICAR reduced the degree of myocardial atrophy, and RNAseq analysis showed that this was driven by normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
2024-11-01 | GSE218397 | GEO
Project description:The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) in addressing heart failure need improvement for a better engraftment and survival. This study explores the role of metabolic sorting for human bmMSC on coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic and gene expression approaches on cells sorted on the mitochondrial membrane potential referring their metabolic status, we demonstrated that bmMSC selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress favoring cell engraftment. Therapeutic use of glycolytic bmMSC rescued left ventricular ejection fraction and decrease fibrosis in mice model of acute heart failure. Metabolic changes were also related to epigenetic histone modifications as lysine methylation. Targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent for enhancing the metabolic profile of bmMSC, we decipher the interplay between glycolysis and cell functionality. Our study leads to elucidate novel strategies for optimizing bmMSC-based therapies in treating heart failure and highlight the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies.
2024-07-31 | GSE251709 | GEO
Project description:Heart failure represents a leading cause of mortality in the elderly population. Although aging features include diastolic dysfunction and interstitial fibrosis in both males and females, it becomes increasingly apparent that aged male and female hearts are phenotypically different. There were fundamental differences in extracellular matrix (ECM) composition and architecture and heart function indices at the baseline, which were further accentuated by Aicar treatment. By combining in vivo, ex vivo, and in vitro strategies, we demonstrated that there are sex-specific features that influence the response to pharmacological intervention in the aging mouse heart.
2022-06-23 | PXD031223 | Pride
Project description:Targeting mitochondrial metabolism for detection and treatment of doxorubicin-induced heart failure
| PRJNA646759 | ENA
Project description:Metabolic conditioning enhances human bmMSC cell therapy of doxorubicin-induced heart failure
| PRJNA1055094 | ENA
Project description:AICAR monophosphate (5-Aminoimidazole-4-carboxamide ribonucleotide) is a metabolic intermediate of the de novo purine synthesis pathway presenting highly promising metabolic and antiproliferative properties. Yeast mutants accumulating AICAR are auxotroph for histidine. A screening for suppressors of this phenotype identified recessive and dominant mutants that result in lowering intracellular AICAR concentration. The recessive mutants affect adenosine kinase which is shown here to catalyze the phosphorylation of AICAR riboside in yeast. The dominant mutants strongly enhance the capacity of the alkaline phosphatase Pho13p to dephosphorylate succinyl-AICAR monophosphate into the non-toxic riboside form. By combining these mutants to transcriptomic and metabolomic analyses, we establish that in yeast both toxic and physiological responses to AICAR are linked to the concentration of the monophosphate form, while the nucleoside moiety has no effect even at high concentration. Finally, we establish that (S)AICAR concentration varies under physiological conditions, thus modulating transcriptional regulation of purine pathway genes. This SuperSeries is composed of the SubSeries listed below.
2011-07-11 | GSE29324 | GEO
Project description:We conducted RNAseq using mRNA extracted from rat hearts to elucidate the effect of doxorubicin chemotherapy on the heart. Rats were 250g at the start of the treatment protocol. Tissues were collected post five weekly intravenous injections of either sterile saline or 3mg/kg/week doxorubicin. Hearts were excised under deep isoflurane anaesthesia and rapidly frozen with liquid-nitrogen cooled Wallenberger tongs. Total mRNA was extracted with a Qiagen RNeasy fibrous tissue mini kit. Gene set enrichement analysis (GSEA) shows that unlike previously reported, oxidative stress is not involved in the cardiac pathology of our model (reduced cardiac function and atrophy). However, gene sets responsible for mRNA processing, ribosomes and protein synthesis and processing are decreased in doxorubicin-treated rat hearts compared to saline control hearts.
2020-11-10 | GSE154603 | GEO
Project description:The purpose of the research is to delineate the mechanism behind AICAR-induced cytotoxicity by understanding the genetic pathways that are affected with AICAR treatment.
2023-02-21 | GSE198777 | GEO
Project description:To identify genes transcriptionally regulated by AICAR under cellular stress, We treated NALM6 cells for 45 min with vehicle (DMSO) or AICAR (15 mM), and examined their RNA profile using RNA-Seq. The immediate early genes (IEGs) were identified as a subset of genes downregulated by AICAR.
2021-07-22 | GSE152917 | GEO
Project description:We aimed to identify gene variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure rats (SHHF) and reference strains. We combined linkage analyses with genome-wide expression profiling .
2008-09-01 | E-TABM-418 | biostudies-arrayexpress