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SGLT2 inhibitor upregulates myocardial genes for oxidative phosphorylation and fatty acid metabolism in Gαq mice (genotype x timepoint)

ABSTRACT: Background. Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the mechanism of this effect is not clear. Objectives. Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq. Methods. Gαq and wild-type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow). Results. From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis – all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU. Conclusions. The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, thereby leading to increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE276289 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:Wollbold2014 - Effects of reactive oxygen species This model is described in the article: Anti-inflammatory effects of reactive oxygen species ¿ a multi-valued logical model validated by formal concept analysis. Wollbold J, Jaster R, Müller S, Rateitschak K, Wolkenhauer O. BMC Syst Biol 2014 Sep; 8(1): 101 Abstract: BackgroundRecent findings suggest that in pancreatic acinar cells stimulated with bile acid, a pro-apoptotic effect of reactive oxygen species (ROS) dominates their effect on necrosis and spreading of inflammation. The first effect presumably occurs via cytochrome C release from the inner mitochondrial membrane. A pro-necrotic effect ¿ similar to the one of Ca2+ ¿ can be strong opening of mitochondrial pores leading to breakdown of the membrane potential, ATP depletion, sustained Ca2+ increase and premature activation of digestive enzymes. To explain published data and to understand ROS effects during the onset of acute pancreatitis, a model using multi-valued logic is constructed. Formal concept analysis (FCA) is used to validate the model against data as well as to analyze and visualize rules that capture the dynamics.ResultsSimulations for two different levels of bile stimulation and for inhibition or addition of antioxidants reproduce the qualitative behaviour shown in the experiments. Based on reported differences of ROS production and of ROS induced pore opening, the model predicts a more uniform apoptosis/necrosis ratio for higher and lower bile stimulation in liver cells than in pancreatic acinar cells. FCA confirms that essential dynamical features of the data are captured by the model. For instance, high necrosis always occurs together with at least a medium level of apoptosis. At the same time, FCA helps to reveal subtle differences between data and simulations. The FCA visualization underlines the protective role of ROS against necrosis.ConclusionsThe analysis of the model demonstrates how ROS and decreased antioxidant levels contribute to apoptosis. Studying the induction of necrosis via a sustained Ca2+ increase, we implemented the commonly accepted hypothesis of ATP depletion after strong bile stimulation. Using an alternative model, we demonstrate that this process is not necessary to generate the dynamics of the measured variables. Opening of plasma membrane channels could also lead to a prolonged increase of Ca2+ and to necrosis. Finally, the analysis of the model suggests a direct experimental testing for the model-based hypothesis of a self-enhancing cycle of cytochrome C release and ROS production by interruption of the mitochondrial electron transport chain. This model is hosted on BioModels Database and identified by: MODEL1407230001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: Inhibitors of sodium glucose linked transporter 2 (SGLT2i) improve heart failure (HF) outcomes in patients independent of diabetes. While animal studies suggest SGLT2i improve cardiac metabolism, the effect of SGLT2i on mitochondrial function in the heart is not known. Our goal was to assess the effects of SGLT2i on mitochondrial function, high energy phosphates and genes encoding mitochondrial proteins in hearts of mice with and without diet-induced diabetes. Methods & Results: Ertugliflozin (Ertu; formulated to 0.5 mg/g of diet) was given for 4 months to mice fed a high fat, high sucrose (HFHS) diet that causes diabetic cardiomyopathy or control diet (CD). Mitochondrial function was measured in isolated cardiac mitochondria. Myocardial energetics were assessed by NMR spectroscopy simultaneously with systolic function in isolated beating hearts. Myocardial gene expression was assessed by RNA seq using gene set enrichment analysis. HFHS diet caused myocardial hypertrophy and diastolic dysfunction, mitochondrial dysfunction (decreased ATP production, increased reactive oxygen species release) and an impaired energetic response to increased work demand - all of which were prevented by Ertu. Conctractile function, as reflected by the rate x pressure product (RPP), was super-normalized to a value 124% of CD hearts at high work demand. In control mice, Ertu had no effect on isolated mitochondria function or high energy phosphates, but similar to HFHS hearts, caused super-normalization of RPP to 125% of CD hearts. By GSEA the highest scoring gene set for Ertu treatment was oxidative phosphorylation (OXPHOS), which was up-regulated across all groups while controlling for diet with a Normalized Enrichment Score (NES) of +3.71, and was similarly up-regulated in HFHS-fed mice (NES, +3.32) and in CD-fed mice (NES, +3.34). Fatty acid metabolism (FAM) was the second-highest scoring gene set for Ertu, and, like OXPHOS, was up-regulated independent of diet (NES, +2.82). Conclusion: The super-normalization of contractile function and induction of the OXPHOS and FAM gene sets by Ertu are independent of diabetic status. Pro-metabolic remodeling of the myocardium by Ertu may support increased contractile function and contribute to the beneficial actions of Ertu in states such as heart failure that are associated with impaired cardiac mitochondrial function.

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SGLT2 inhibitor upregulates myocardial genes for oxidative phosphorylation and fatty acid metabolism in Gαq mice (genotype x timepoint)

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