Luseogliflozin inhibits high glucose-induced TGF-<b>β</b>2 expression in mouse cardiomyocytes by suppressing NHE-1 activity

Osaka, Naoya; Mori, Yusaku; Terasaki, Michishige; Hiromura, Munenori; Saito, Tomomi; Yashima, Hideaki; Shiraga, Yoshie; Kawakami, Raichi; Ohara, Makoto; Fukui, Tetsuya; Yamagishi, Sho‐ichi

doi:10.1177/03000605221097490

Cited by 11 publications

(7 citation statements)

References 41 publications

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“… 66 , 67 The published interchange between the 2 groups revealed that the data of Chung et al 69 were derived from a larger sample size. 68 , 69 Osaka et al 70 claimed that SGLT2 inhibition inhibited NHE1, but the effect was substantially less than that seen with cariporide. Li et al 48 failed to show meaningful docking of empagliflozin to NHE1 and reported that cariporide did not mimic the action of the SGLT2 inhibitor on isolated cardiomyocytes.…”

Section: Potential Actions Of Sglt2 Inhibitors To Inhibit Sodium-hydr...mentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

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Section: Potential Actions Of Sglt2 Inhibitors To Inhibit Sodium-hydr...mentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

View full text Add to dashboard Cite

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“…Furthermore, SGLT2is alleviate vascular permeability and mitochondrial Ca 2+ overload [ 99 ]. According to the study of Osaka et al, hyperglycaemic-stimulated NHE-1 activity was reversed via luseogliflozin in mice cardiomyocytes, which resulted in the attenuation of TGF-β2 expression and mitigation of cardiomyocyte hypertrophy and fibrosis [ 102 ].…”

Section: Sglt-2is In Dc—the Overview Of Research Resultsmentioning

confidence: 99%

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

et al. 2022

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According to the 2021 report of the International Diabetes Federation (IDF), there have been approximately 573 million cases of type 2 diabetes mellitus (T2DM) among adults, which sets the disease as a major concern in healthcare worldwide. The development of T2DM is strongly promoted by unhealthy lifestyle factors associated with urbanization and western civilization. The disease is associated with a broad list of systemic complications that can result in premature death, disability and significantly reduced quality of life. The most dramatic in their consequences are cardiovascular complications of T2DM. Our work focuses on one such complication that is specific for diabetes, named diabetic cardiomyopathy (DC). In this condition cardiac dysfunction occurs despite the absence of underlying hypertension, coronary artery disease and valvular disease, which suggest a leading role for metabolic disturbances as a cause. We aimed to establish the role of relatively new hypoglycaemic drugs that have taken the medical world by storm with their broad pleiotropic effects—SGLT-2 inhibitors—in the prevention and treatment of DC at any stage.

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“…According to KEGG pathway analysis, the 6 signaling pathways enriched by tRF-21-NB8PLML3E are mainly related to metabolism. It is generally accepted that the disorder of the cardiac metabolic process is the common pathogenesis factor of PCH [29,30]. It has been shown that impaired adaptation of energy metabolism can exacerbate pathological hypertrophy and increase cardiomyocyte death [31].…”

Section: Discussionmentioning

confidence: 99%

Global Profile of tRNA-Derived Small RNAs in Pathological Cardiac Hypertrophy Plasma and Identification of tRF-21-NB8PLML3E as a New Hypertrophy Suppressor

Xu¹,

Qian²,

Wang³

et al. 2023

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Background: It remains unclear whether transfer RNA-derived small RNAs (tsRNAs) play a role in pathological cardiac hypertrophy (PCH). We aimed to clarify the expression profile of tsRNAs and disclose their relationship to the clinical phenotype of PCH and the putative role. Methods: Small RNA sequencing was performed in the plasma of PCH patients and healthy volunteers. In a larger sample size and angiotensin Ⅱ (Ang II)-stimulated H9c2 cells, the data were validated by real-time qPCR. The atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were examined in Ang II-stimulated H9c2 cells. The role of tsRNAs in the pathogenesis of PCH was explored by bioinformatics analysis. Results: A total of 4185 differentially expressed tsRNAs were identified, of which 4 and 5 tsRNAs were observed to be significantly differentially upregulated and downregulated expressed. Of the 5 down-regulated tsRNAs, 4 of them were verified to be significantly down-regulated in the larger sample group, among which tRF-30-3JVIJMRPFQ5D, tRF-16-R29P4PE, tRF-21-NB8PLML3E, and tRF-21-SWRYVMMV0 had areas under the curve to diagnose concentric hypertrophy. The 4 down-regulated tsRNAs were negatively correlated with left ventricular posterior wall dimensions in PCH patients (r=-0.4227; r=-0.4517; r=-0.5567; r=-0.4223). The levels of ANP and BNP as well as cell size were decreased in Ang II-stimulated H9c2 cells with 21-NB8PLML3E mimic transfection. Bioinformatics analysis revealed that the target genes of tRF-21-NB8PLML3E were mainly enriched in the metabolic pathway and involved in the regulation of ribosomes. Conclusion: The plasma tsRNAs tRF-21-NB8PLML3E might be considered biomarkers in patients with PCH with early screening potential.

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Luseogliflozin inhibits high glucose-induced TGF-β2 expression in mouse cardiomyocytes by suppressing NHE-1 activity

Cited by 11 publications

References 41 publications

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

Global Profile of tRNA-Derived Small RNAs in Pathological Cardiac Hypertrophy Plasma and Identification of tRF-21-NB8PLML3E as a New Hypertrophy Suppressor

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