bims-hafaim 2025-05-04 papers

Issue of 2025–05–04
five papers selected by
Kyle McCommis, Saint Louis University

J Mol Cell Cardiol Plus. 2025 Jun;12 100296

SGLT2 inhibitor upregulates myocardial genes for oxidative phosphorylation and fatty acid metabolism in Gαq-mice.

Jordan M Chambers, Dominique Croteau, David R Pimentel, Adam C Gower, Marcello Panagia, Tomas Baka, Fuzhong Qin, Ivan Luptak, Wilson S Colucci.

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 effect on mitochondria 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, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.

Keywords: Cardiac metabolism; Cardiomyopathy; Energetics; Heart failure with reduced ejection fraction; Mitochondria; Sodium-glucose linked transporter 2 inhibitor

DOI: https://doi.org/10.1016/j.jmccpl.2025.100296

Geroscience. 2025 May 01.

The effect of enhanced glycolysis on cardiac aging.

Anna Faakye, Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Maria F Mendez Garcia, Brooke L Loveland, Sandra N Rigsby, Frederick F Peelor, Craig Eyster, Benjamin F Miller, Timothy M Griffin, Michael Kinter, Ying Ann Chiao, Kenneth M Humphries.

Cardiac aging is associated with metabolic changes, including an increased reliance on glycolysis, and an increased susceptibility to cardiovascular diseases. This study explores the relationship between enhanced cardiac glycolysis and aging using the GlycoHi mouse model, characterized by constitutively elevated glycolysis. We compared cardiac function, metabolism, mitochondrial performance, and hallmarks of aging between aged (21 and 24 months) GlycoHi and wild-type (WT) mice across sexes. Our findings reveal modest reductions in cardiac function in aged GlycoHi mice compared to WT mice, with sex-specific differences in heart size and collagen concentration. Female GlycoHi hearts exhibited hypertrophy without fibrosis, while males showed elevated collagen levels. Whole-body metabolic assessments revealed similar energy expenditure and respiratory patterns across genotypes, with females displaying less circadian-associated variation in metabolism. Mitochondrial analyses showed that aged GlycoHi hearts maintained metabolic adaptations favoring glycolysis but did not exhibit significant bioenergetic dysfunction or oxidative stress. Pyruvate dehydrogenase activity, initially elevated in younger GlycoHi hearts, normalized to WT levels with age. Proteomic and metabolomic analyses highlighted distinct profiles between genotypes, with GlycoHi hearts exhibiting increased glycolytic enzyme levels and reduced abundance of fatty acid oxidation proteins. Despite these differences, indicators of oxidative stress, proteostasis, and cellular senescence were comparable between genotypes, suggesting no acceleration of aging-related dysfunction. This study demonstrates that increased cardiac glycolysis alone does not suffice to drive accelerated cardiac aging. Instead, metabolic and functional changes in aged GlycoHi hearts reflect adaptations rather than pathological declines, providing insights into potential metabolic targets for interventions against cardiac aging.

Keywords: Cardiac aging; Glycolysis; Mitochondria; Oxidative stress; Proteostasis

DOI: https://doi.org/10.1007/s11357-025-01656-z

Cell Physiol Biochem. 2025 Apr 30. 59(2): 235-251

Dapagliflozin, An SGLT2 Inhibitor, Improves Endothelial Cell Energy Metabolism Through Enhanced Mitochondrial Respiration.

Iga Walczak, Alicja Braczko, Aleksandra Paterek, Filip Rolski, Krzysztof Urbanowicz, Maria Tarnawska, Roksana Knapczyk, Aleksandra Parzuchowska, Ryszard T Smoleński, Marcin Hellmann, Michał Mączewski, Barbara Kutryb-Zając.

BACKGROUND/AIMS: Flozins (sodium-glucose cotransporter 2 inhibitors, SGLT2i) are a new class of antidiabetic drugs that reduce cardiovascular mortality and hospitalization rates in heart failure, regardless of type 2 diabetes status. Besides lowering glycemia by inhibiting renal glucose reabsorption, SGLT2 inhibitors may exert sodium-dependent hemodynamic effects and improve cardiomyocyte energy metabolism, substrate preference, and mitochondrial function. However, their impact on endothelial cells remains largely unknown. This study aimed to analyse the effects and mechanisms of SGLT2i on endothelial cell metabolism and function.
METHODS: Mouse cardiac endothelial cells (H5V) were used to test the impact of dapagliflozin on endothelial cell metabolism and function in the presence of hypoxia-mimicking conditions. The concentration of intracellular nucleotides was measured using high-performance liquid chromatography. Mitochondrial and glycolytic activity were assessed using Seahorse XFp, while nitric oxide (NO) production was determined by 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) fluorescence staining. The effects of dapagliflozin treatment on endothelial NO synthesis were also analysed in patients with chronic heart failure and left ventricular ejection fraction above 40% and C57Bl/6J mice.
RESULTS: Dapagliflozin augmented adenosine triphosphate (ATP) levels and the ATP/ADP (adenosine diphosphate) ratio in cultured endothelial cells correlated to increased NO production. Dapagliflozin-treated endothelial cells produced ATP through both mitochondrial respiration and glycolysis. Interestingly, mitochondrial respiration was enhanced, while glycolysis was unaffected in endothelial cells after in vitro dapagliflozin treatment. In a murine model, dapagliflozin doubled the rate of coronary NO synthesis and tended to improve coronary capillary density. In humans with chronic heart failure, 3-month treatment with dapagliflozin revealed many metabolic effects, suggesting potential mechanisms related to nitric oxide homeostasis, mitochondrial function, and L-arginine metabolism.
CONCLUSION: This study demonstrated the beneficial effect of dapagliflozin on endothelial cell metabolism and function. Regulation of endothelial cell bioenergetics may be an undervalued mechanism of SGLT2i to delay heart failure progression and support cardiac regeneration. These may accelerate endothelial-targeted strategies to support heart failure treatment.

Keywords: Dapagliflozin; Cardiac endothelial cells; Nitric oxide; Energy metabolism

DOI: https://doi.org/10.33594/000000772

Nat Commun. 2025 Apr 26. 16(1): 3933

Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice.

The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO2-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO2-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO2-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5'-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO2-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO2-OA may represent a promising therapeutic strategy for HFpEF.

DOI: https://doi.org/10.1038/s41467-025-59192-5

Life Sci. 2025 Apr 24. pii: S0024-3205(25)00293-0. [Epub ahead of print]373 123658

Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy.

Sin-Jin Li, Laura H Tetri, Vijith Vijayan, Aly Elezaby, Chun-Hsien Chiang, Ivan Lopez, Nicolai P Ostberg, Timothy T Cornell, Ching-Yi Chen, Bereketeab Haileselassie.

AIMS: Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.
MATERIALS AND METHODS: H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.
KEY FINDINGS: PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release in vitro. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. In vivo, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both in vitro and in vivo.
SIGNIFICANCE: P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.

Keywords: Extracellular mitochondria; Fission; Lipotoxicity; Mitochondrial dynamics; Obesity cardiomyopathy; P110

DOI: https://doi.org/10.1016/j.lfs.2025.123658