Abstract 16641: The SGLT2 Inhibitor Ertugliflozin Induces Oxidative Phosphorylation Gene Expression and Improves Systolic Function Independent of Diabetes in Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dominique Croteau ◽  
Ivan Luptak ◽  
Fuzhong Qin ◽  
Jordan M Chambers ◽  
Ion A Hobai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Systolic Function ◽  
High Energy ◽  
Enrichment Score ◽  
High Energy Phosphates ◽  
Gene Set ◽  
Work Demand ◽  
Myocardial Gene Expression

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; 0.5 mg/g) 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 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. Systolic 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. Myocardial gene expression analysis revealed oxidative phosphorylation (OXPHOS) as the top scoring gene set that was both down-regulated by HFHS with a normalized enrichment score (NES) of -2.08, and up-regulated by Ertu in HFHS (NES, +3.32 vs HFHS). OXPHOS was the top scoring gene set up-regulated by Ertu a) across all groups while controlling for diet (NES, +3.71) and b) in CD-fed mice only (NES, +3.34). Conclusion: The super-normalization of systolic function and induction of the OXPHOS gene set by Ertu is independent of diabetic status. Pro-metabolic remodeling of the myocardium by Ertu may support increased systolic function and contribute to the beneficial actions of Ertu in states such as HF that are associated with impaired cardiac mitochondrial function.

scholarly journals Impaired Cerebral Mitochondrial Oxidative Phosphorylation Function in a Rat Model of Ventricular Fibrillation and Cardiopulmonary Resuscitation

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jun Jiang ◽  
Xiangshao Fang ◽  
Yue Fu ◽  
Wen Xu ◽  
Longyuan Jiang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Fibrillation ◽  
Cardiopulmonary Resuscitation ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Rat Model ◽  
Mitochondrial Function ◽  
High Energy ◽  
Mitochondrial Morphology ◽  
High Energy Phosphates

Postcardiac arrest brain injury significantly contributes to mortality and morbidity in patients suffering from cardiac arrest (CA). Evidence that shows that mitochondrial dysfunction appears to be a key factor in tissue damage after ischemia/reperfusion is accumulating. However, limited data are available regarding the cerebral mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) and its relationship to the alterations of high-energy phosphate. Here, we sought to identify alterations of mitochondrial morphology and oxidative phosphorylation function as well as high-energy phosphates during CA and CPR in a rat model of ventricular fibrillation (VF). We found that impairment of mitochondrial respiration and partial depletion of adenosine triphosphate (ATP) and phosphocreatine (PCr) developed in the cerebral cortex and hippocampus following a prolonged cardiac arrest. Optimal CPR might ameliorate the deranged phosphorus metabolism and preserve mitochondrial function. No obvious ultrastructural abnormalities of mitochondria have been found during CA. We conclude that CA causes cerebral mitochondrial dysfunction along with decay of high-energy phosphates, which would be mitigated with CPR. This study may broaden our understanding of the pathogenic processes underlying global cerebral ischemic injury and provide a potential therapeutic strategy that aimed at preserving cerebral mitochondrial function during CA.

Neutrophils Derived from Ezh2 -/- Progenitor Cells Demonstrate Aberrant Erythroid Lineage Gene Expression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4112-4112
Author(s):  
Albert Perez-Ladaga ◽  
Huafeng Xie ◽  
Stuart H. Orkin ◽  
David B. Sykes ◽  
Benjamin L. Ebert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Gene Expression Profiling ◽  
Progenitor Cells ◽  
Expression Profiling ◽  
Gene Set ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Estrogen Withdrawal ◽  
Functional Defects

Abstract Introduction: Ezh2 is the catalytic component of the polycomb repressive complex 2, which methylates lysine 27 of histone H3 (H3K27). Loss of function mutations in EZH2 are found in 6% of MDS patients and are independently associated with worse overall survival compared to patients with wildtype EZH2 (Bejar R. et al., 2011 and 2012). Our group has described that neutrophils derived from Ezh2-/- mice have functional defects (Perez-Ladaga et al., 2013), including decreased phagocytosis, aberrant migration and overproduction of reactive oxygen species (ROS). To determine how loss of Ezh2 might contribute to these functional deficits, we performed gene expression profiling on immortalized myeloid cell lines capable of neutrophilic differentiation. Methods: Bone marrow from Ezh2 null (Ezh2-/-) and littermate control mice (WT) were transduced with HOXB8 fused to the estrogen receptor ligand-binding domain to produce immortalized myeloid progenitor cells. Removal of estrogen from the media allows these cells differentiate into mature neutrophils (Wang G.G., 2006). RNA from progenitor and mature neutrophils (WT and Ezh2-/-) was extracted each condition in duplicate and subjected to gene expression profile (Affymetrix). Transcriptome analysis was conducted with TAC software from Affymetrix and gene set comparisons between the different phenotypes were analyzed with Gene Set Enrichment Analysis (GSEA). Rescue by lentiviral re-introduction of Ezh2 into Ezh2-/- cells is currently ongoing. Results: Estrogen withdrawal causes differentiation of WT and Ezh2-/- lines into mature neutrophils after six days. Interestingly, WT neutrophils lose Ezh2 mRNA and protein expression as soon as three days after estrogen withdrawal. WT mature neutrophils lack Ezh2 and trimethyl-H3K27 (me3H3K27), showing similar amounts as Ezh2-/- derived neutrophils. Gene expression profiling of 65956 transcripts demonstrated that 1953 of them were differentially expressed between WT and Ezh2-/- mature neutrophils. Nearly 65% of these genes were upregulated in Ezh2-/- derived neutrophils when compared to WT. As Ezh2 levels in mature neutrophils are similar in both conditions, gene expression differences are likely due to EZH2 and me3H3K27 differences in the progenitor state. Among the differentially expressed genes, the transcription factor GATA1 was found upregulated in Ezh2-/- derived neutrophils, a result confirmed by qPCR. GATA1 regulates the expression of hundreds of genes and is essential for erythropoiesis. GATA1 target erythroid genes were also found upregulated in Ezh2-/- derived neutrophils when compared to WT, while no significant differences in neutrophil gene expression were detected. Similarly, GSEA analysis of Ezh2-/- vs. WT confirmed strong enrichment for erythroid associated expression programs. A Heme Metabolism Signature based on a panel of 182 genes showed a strong correlation with Ezh2-/- derived neutrophils (Figure 1A). GSEA was used to examine possible mechanisms behind the functional defects previously reported in Ezh2-/- derived neutrophils such as overproduction of ROS and impaired migration. A gene set based on 192 genes encoding proteins involved in oxidative phosphorylation demonstrated a significant correlation between this pathway signature and Ezh2-/- derived neutrophils (Figure 1B).On the other hand, GSEA showed a positive correlation between WT differentiated neutrophils and a panel of 115 genes involved in leukocyte transendothelial migration (Figure 1C). Conclusion: Our results show that HOXB8-ER immortalized myeloid progenitor cells are able to produce mature neutrophils even in absence of Ezh2. The loss of Ezh2 in myeloid progenitor cells is associated with the differential expression of 1953 genes in mature neutrophils, including the upregulation of genes involved in erythroid differentiation programs and oxidative phosphorylation, and the downregulation of genes involved in leukocyte migration. Ongoing rescue experiments re-introducing Ezh2 into Ezh2-/- progenitor cells are being performed to determine if this restores normal neutrophil functions and silences the aberrant erythroid gene expression in Ezh2-/- derived neutrophils. Our findings may help explain how Ezh2 loss causes neutrophil dysfunction and contributes to the adverse prognosis associated with EZH2 mutations in MDS patients. Disclosures Orkin: Editas Inc.: Consultancy. Ebert:genoptix: Consultancy, Patents & Royalties; Celgene: Consultancy; H3 Biomedicine: Consultancy. Bejar:Alexion: Other: ad hoc advisory board; Celgene: Consultancy, Honoraria; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature.

Effects of inotropic stimulation on energy metabolism and systolic function of ischemic right ventricle

1995 ◽  
Vol 268 (5) ◽  
pp. H1821-H1828 ◽  
Author(s):  
C. Greyson ◽  
J. Garcia ◽  
M. Mayr ◽  
G. G. Schwartz
Keyword(s):  
Energy Metabolism ◽  
Right Ventricle ◽  
High Speed ◽  
Systolic Function ◽  
Venous Blood ◽  
Lactate Production ◽  
High Energy ◽  
High Energy Phosphates ◽  
Free Wall ◽  
High Energy Phosphate

This study determined whether dobutamine enhances regional systolic function in the ischemic right ventricle (RV) at the cost of adverse effects on regional energy metabolism. Seventeen alpha-chloralose-anesthetized, open-chest pigs were studied under four conditions: 1) control; 2) dobutamine infusion (mean dose 9 micrograms.kg-1.min-1); 3) RV ischemia (45 +/- 5% reduction in RV free wall blood flow for 100 min); and 4) continued ischemia with dobutamine. Regional RV free wall high-energy phosphate metabolites were measured by 31P nuclear magnetic resonance (NMR) spectroscopy or by high-speed drill biopsies of the RV free wall. Regional RV free wall substrate and O2 consumption were measured using coronary venous blood sampling. Global RV systolic function was assessed by the maximal first derivative of RV pressure (dP/dtmax), and regional RV free wall systolic function was assessed by systolic segment shortening in the ischemic zone. Right coronary artery constriction caused markedly depressed regional RV systolic function, net lactate production, and coronary venous acidosis. Surprisingly, high-energy phosphates were unchanged compared with control. Addition of dobutamine caused a further decline in coronary venous pH and continued lactate production but did not reduce high-energy phosphates. While dobutamine markedly enhanced global RV systolic function (RV dP/dtmax 201 +/- 19% of control), systolic shortening in the ischemic RV free wall remained severely depressed (47 +/- 18% of control) despite dobutamine. The mechanism of high-energy phosphate preservation is likely due to diminished consumption of ATP in the hypocontractile ischemic region.

Effect of Sympathectomy and Vagotomy on Carbonic Anhydrase Activity, Oxidative Phosphorylation, High Energy Phosphates Content and Electrolytes Content of the Gastric Mucosa

1958 ◽  
Vol 192 (3) ◽  
pp. 476-478 ◽  
Author(s):  
Takeshi Yakushiji ◽  
Tetsuya Kikuchi ◽  
Junichi Yamamoto ◽  
Kaname Kuriaki
Keyword(s):  
Gastric Mucosa ◽  
Carbonic Anhydrase ◽  
Oxidative Phosphorylation ◽  
High Energy ◽  
Carbonic Anhydrase Activity ◽  
High Energy Phosphates

Sympathectomy enhanced carbonic anhydrase activity, increased the rate of oxidative phosphorylation and the ATP and potassium contents of the canine gastric mucosa. Vagotomy was essentially without effect.

scholarly journals Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Richard C. Chang ◽  
Kara N. Thomas ◽  
Nicole A. Mehta ◽  
Kylee J. Veazey ◽  
Scott E. Parnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Chromatin Structure ◽  
Alcohol Exposure ◽  
Structural Defects ◽  
Congenital Defects ◽  
Sequencing Analysis ◽  
Oxidative Homeostasis

Abstract Background A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Results Deep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression. Conclusions Our studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.

scholarly journals Effects of Sodium‐Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice

2021 ◽  
Author(s):  
Dominique Croteau ◽  
Ivan Luptak ◽  
Jordan M. Chambers ◽  
Ion Hobai ◽  
Marcello Panagia ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
High Energy ◽  
Contractile Reserve ◽  
High Energy Phosphates ◽  
Cardiac Energetics ◽  
High Fat ◽  
Gene Sets ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
High Sucrose

Background Inhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31 P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Conclusions Ertugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.

Relation among regional O2 consumption, high-energy phosphates, and substrate uptake in porcine right ventricle

1994 ◽  
Vol 266 (2) ◽  
pp. H521-H530 ◽  
Author(s):  
G. G. Schwartz ◽  
C. R. Greyson ◽  
J. A. Wisneski ◽  
J. Garcia ◽  
S. Steinman
Keyword(s):  
Oxidative Phosphorylation ◽  
Myocardial Oxygen Consumption ◽  
High Energy ◽  
Substrate Uptake ◽  
High Energy Phosphates ◽  
The Right ◽  
Pulmonary Artery Constriction ◽  
Isoproterenol Infusion ◽  
Alternative Stimulus

Changes in phosphate metabolites may play a role in the regulation of myocardial oxidative phosphorylation in vivo. We tested the hypothesis that changes in phosphate metabolites with increased myocardial oxygen consumption (MVO2) depend on the mechanism by which MVO2 is increased. In 17 open-chest pigs, regional MVO2 of the right ventricular (RV) free wall was increased from control by isoproterenol infusion (Iso) and by pulmonary artery constriction (PAC). The phosphocreatine-to-ATP ratio (PCr/ATP), which is inversely related to free ADP concentration ([ADP]), was determined by 31P-nuclear magnetic resonance (NMR) spectroscopy. Regional MVO2 and lactate, glucose, and free fatty acid (FFA) uptake were determined in the myocardium directly beneath the NMR coil. Iso and PAC increased MVO2 nearly equally, to approximately twice control, but produced directionally opposite changes in PCr/ATP: a significant decrease with PAC (control 1.52 +/- 0.06, PAC 1.35 +/- 0.06, means +/- SE) but a significant increase with Iso (to 1.72 +/- 0.07). Thus increased [ADP] may have stimulated oxidative phosphorylation during PAC but could not have done so during Iso. With Iso, uptake of FFA was more than three times that with PAC, and the sum of the oxygen extraction ratios for lactate, glucose, and FFA was more than double that with PAC. Enhanced substrate uptake during Iso may have increased mitochondrial NADH, which in turn may have provided an alternative stimulus to the rate of oxidative phosphorylation. These results support multifactorial control of RV oxidative phosphorylation in vivo.

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