Dapagliflozin Attenuates Myocardial Fibrosis by Inhibiting the TGF-β1/Smad Signaling Pathway in a Normoglycemic Rabbit Model of Chronic Heart Failure

Chen, Xuefeng; Yang, Qian; Bai, Wenlou; Yao, Wenli; Liu, Litian; Yuanyuan, Xing; Meng, Cunliang; Peng, Qi; Dang, Yi; Qi, Xiaodan

doi:10.3389/fphar.2022.873108

Cited by 12 publications

(9 citation statements)

References 52 publications

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“…Comparably, SMIT has been reported to be an important driver of acute myeloid leukemia cell 20 proliferation 61 and pharmacological inhibition with phlorizin, the substance DAPA and EMPA are derived from, led to reduced proliferation and migration of lung cancer cells 62 . Based on the described reduction in effect size of SGLT2is on HCF proliferation upon respective KD, we conclude that antifibrotic cardiovascular effects of SGLT2is [63][64][65] are mediated through their direct binding and inhibition of SMIT, SMVT, and NHE1.…”

Section: Discussionmentioning

confidence: 70%

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

Schmidt,

Groß

et al. 2023

Preprint

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Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells (HUVECs). Proteomics analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performedin vitroEndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts (HCFs) exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.

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Section: Discussionmentioning

confidence: 70%

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

Schmidt,

Groß

et al. 2023

Preprint

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“…Multiple studies in the past 2 decades show that dysregulated mTORC1 plays a critical role in the pathophysiology of kidney diseases, NAFLD, cardiovascular and neuronal disorders, and cancer ( 23 – 25 , 40 ). Fine-tuned, moderate inhibition of mTORC1 is beneficial in that it reduces the cellular workload and stimulates autophagy and mitophagy, which improve protein and organelle quality control, thereby reducing cellular stress and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple studies in the past two decades showed that dysregulated mTORC1 plays a critical role in the pathophysiology of kidney diseases, NAFLD, cardiovascular and neuronal disorders as well as cancer (23)(24)(25)40).…”

Section: Implications Of Mtorc1 Inhibition For Diabetes Complications...mentioning

confidence: 99%

“…Furthermore, in both normoglycemic and diabetic animals, treatment with SGLT2i resulted in accumulation of the glycolytic intermediates dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GA3P) in liver and kidney; this was associated with inhibition of the rate-limiting glycolytic enzyme pyruvate kinase in the liver. Importantly, SGLT2i increased glucose/pyruvate oxidation in the TCA cycle, activated AMPK and inhibited the nutrient sensor mTORC1 in all organs; this probably explains the protective effects on the kidney, heart and probably the liver (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Kogot-Levin¹,

Riahi²,

Abramovich³

et al. 2023

JCI Insight

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Diabetes is associated with increased risk for kidney and liver diseases, congestive heart failure, and mortality. Urinary glucose excretion using sodiumglucose cotransporter 2 (SGLT2) inhibitors prevents these adverse outcomes, however the mechanisms involved are not clear. Herein, we generated a roadmap of the metabolic alterations that occur in the kidney, liver, and heart in diabetes and in response to SGLT2 inhibition. We performed in vivo metabolic labeling with 13 C-glucose in normoglycemic and diabetic mice treated with or without the SGLT2 inhibitor dapagliflozin, followed by simultaneous metabolomics and metabolic flux analyses in different organs and the plasma.We found that in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis and further inhibited pyruvate kinase activity in the liver. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this effect was associated with modulation of the redox state, which may protect against oxidative stress. In addition, diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues with implications for diabetes and aging.

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“…Finally, although there are clinical data showing that sodium-glucose cotransporter-2 inhibitors reduce BP 59 and LVM, 60,61 and experimental data showing their ability to attenuate MIF, 62 no evidence is still available on their effects on either PICP or ECV and on their effectiveness to reduce the risk of HF in HHD.…”

Section: Preventive and Therapeutic Aspectsmentioning

confidence: 99%

Growing Heart Failure Burden of Hypertensive Heart Disease: A Call to Action

Díez

Butler

2023

Hypertension

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Hypertensive heart disease (HHD) is currently the second leading cause of heart failure (HF). The prevalence of HHD and its associated risk of heart failure have increased despite substantial improvement in arterial hypertension treatment and control in the recent decades. Therefore, the prevention of heart failure in patients with HHD represents an unmet medical need, due to its clinical, economic, and social impact. In this conceptual framework, we call to action because the time has come for diagnosis and treatment of patients with HHD not to be limited to assessment of morphological and functional left ventricular changes, blood pressure control, and left ventricular hypertrophy regression. We propose a further perspective incorporating also the detection and reversal of the histological changes that develop in the hypertensive heart and that lead to the structural remodeling of the myocardium. In particular, we focus on the diagnosis and treatment of myocardial interstitial fibrosis, likely the lesion most critically involved in the transition from subclinical HHD to clinically overt heart failure. In this context, it is worth considering whether the use of imaging and circulating biomarkers for the noninvasive diagnosis of myocardial interstitial fibrosis should be incorporated in the medical study of hypertensive patients, especially of those with HHD.

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Dapagliflozin Attenuates Myocardial Fibrosis by Inhibiting the TGF-β1/Smad Signaling Pathway in a Normoglycemic Rabbit Model of Chronic Heart Failure

Cited by 12 publications

References 52 publications

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Growing Heart Failure Burden of Hypertensive Heart Disease: A Call to Action

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