Inhibition of HMOX1 alleviates diabetic cardiomyopathy by targeting ferroptosis
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ABSTRACT:
PROVIDER: PRJNA1006668 | ENA |
REPOSITORIES: ENA
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Project description:Diabetic cardiomyopathy (DCM) is an important complication of chronic diabetes mellitus (DM). However, its pathogenesis and pathologic process have not been fully elucidated. This study was aimed to investigate the role of ferroptosis in the pathogenesis of DCM and clarify the effect of HMOX1 on DCM by targeting ferroptosis. DCM mouse model was constructed by high fat diet (HFD) feeding and streptozotocin (STZ). injection.
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Project description:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2, a core microRNA, remain elusive. We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes mellitus and diabetic cardiomyopathy. Ago2 decreased in cardiomyocyte mitochondria in both models. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain (ETC) subunits and decrease reactive oxygen species. Malonylation, a post-translational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. Our results reveal that the SIRT3–Ago2–CYTB axis links glucotoxicity to cardiac ETC imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.
2024-09-27 | GSE242088 | GEO
Project description:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2, a core microRNA, remain elusive. We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes mellitus and diabetic cardiomyopathy. Ago2 decreased in cardiomyocyte mitochondria in both models. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain (ETC) subunits and decrease reactive oxygen species. Malonylation, a post-translational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. Our results reveal that the SIRT3–Ago2–CYTB axis links glucotoxicity to cardiac ETC imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.
2024-09-27 | GSE242185 | GEO
Project description:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2, a core microRNA, remain elusive. We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes mellitus and diabetic cardiomyopathy. Ago2 decreased in cardiomyocyte mitochondria in both models. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain (ETC) subunits and decrease reactive oxygen species. Malonylation, a post-translational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. Our results reveal that the SIRT3–Ago2–CYTB axis links glucotoxicity to cardiac ETC imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.
2024-09-27 | GSE242024 | GEO
Project description:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular Ago2, a core microRNA, remain elusive. We elucidated the function and mechanism of subcellular localized Ago2 on mouse models for diabetes mellitus and diabetic cardiomyopathy. Ago2 decreased in cardiomyocyte mitochondria in both models. Overexpression of mitochondrial Ago2 attenuated diabetes-induced cardiac dysfunction. Ago2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain (ETC) subunits and decrease reactive oxygen species. Malonylation, a post-translational modification of Ago2, reduced the importing of Ago2 into mitochondria in diabetic cardiomyopathy. Ago2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. Our results reveal that the SIRT3–Ago2–CYTB axis links glucotoxicity to cardiac ETC imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.
2024-09-27 | GSE241911 | GEO
Project description:Diabetic cardiomyopathy (DCM) is a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Exploring the transcriptomics and proteomics of DCM is of great significance for understanding the biology of the disease and for guiding new therapeutic targets for the potential therapeutic effect of spermine (SPM).
2022-01-24 | GSE161052 | GEO
Project description:Activation of the systemic and myocardial rennin-angiotensin-aldosterone system (RAAS) by hyperglycemia plays a critical role in the development of diabetic cardiomyopathy. To test the hypothesis that AngIV protects against diabetic cardiomyopathy via stimulation of AT4R and inhibition of overactive autophagy, diabetic mice were treated with low-, medium- and high-dose AngIV, AT4R antagonist divalinal, forkhead box protein O1 (FoxO1) inhibitor AS1842856 (AS) or their combinations. In vitro, cardiomyocytes were treated with different concentrations of glucose, low-, medium- and high-dose AngIV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS or their combinations. The results showed that AngIV treatment dose-dependently attenuated left ventricular dysfunction, remodeling, fibrosis, and myocyte apoptosis in diabetic mice. Besides, autophagy and FoxO1 protein expression enhanced by diabetes were dose-dependently suppressed by AngIV treatment. However, these cardioprotective effects of AngIV were completely abolished by divalinal administration. Bioinformatic analyses revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose AngIV groups. Similar to AngIV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, AngIV inhibited collagen expression, apoptosis, overactive autophagy flux, and FoxO1 nuclear translocation induced by high glucose in cardiomyocytes. However, these protective effects of AngIV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. In summary, AngIV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanism involved stimulation of AT4R, suppression of FoxO1 nuclear translocation and inhibition of FoxO1-mediated overactive autophagy.
2020-07-30 | GSE155377 | GEO
Project description:Diabetic cardiomyopathy (DCM) is one of the major causes of heart failure in diabetic patients, but its pathogenesis remains unclear. Long non-coding RNAs (lncRNAs) are involved in the development of various cardiovascular diseases, but is little known in DCM. We build diabetic cardiomyopathy (DCM) rat model and investigated the genome-wide expression profiling of cardiac lncRNAs and mRNAs in rat model with and without DCM by RNA sequencing, to uncovers potential path mechanisms target of DCM.
2022-03-13 | GSE197999 | GEO
Project description:Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.
2023-10-24 | PXD044236 | Pride