Empagliflozin enhances human and murine cardiomyocyte glucose uptake by increased expression of GLUT1

Mustroph, Julian; Lücht, Charlotte M.; Wagemann, Olivia; Sowa, Thomas; Hammer, K; Sag, Can Martin; Tarnowski, Daniel; Holzamer, Andreas; Pabel, Steffen; Beuthner, Bo Eric; Sossalla, Samuel; Maier, Lars S.; Wagner, Stefan

doi:10.1007/s00125-019-4819-z

Cited by 18 publications

(13 citation statements)

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“…1 Surprisingly, large clinical trials have shown a reduced incidence of hospitalization for heart failure (HF) and cardiovascular death in diabetic as well as non-diabetic patients treated with gliflozins. Numerous potential mechanisms were proposed 4 including direct cardiac effects [inhibition of cardiac Ca/calmodulin-dependent protein kinase II (CaMKII)], 5 effects on contractile and myofilament function, 6,7 up-regulation of cardiac glucose transporter 1 (GLUT1) 8 as well as metabolic changes. 9,10 However, the cardiac target for these drug effects remains elusive, especially because cardiac SGLT2 expression is negligible.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

et al. 2020

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Aims Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na + /H + exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. Methods and results Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH 4 + pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 μmol/L, 10 min). Conclusions This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.

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Section: Introductionmentioning

confidence: 99%

Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

et al. 2020

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“…11 Further research regarding the role of these transporters is urgently warranted, especially regarding the potential effects of gliflozins in COVID-19, which have been reported to affect both NHE1 and GLUT1. 4,7 Potential limitations of our study include the low number of diabetic patients in the COVID-19 group, as diabetic patients are at increased risk of mortality when contracting SARS-CoV-2. Also, we could not investigate the effects of gliflozins on GLUT1 and NHE1 in COVID-19 patients, which will need to be addressed in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Further research regarding the role of these transporters is urgently warranted, especially regarding the potential effects of gliflozins in COVID‐19, which have been reported to affect both NHE1 and GLUT1 4,7 …”

Section: Discussionmentioning

confidence: 99%

“…It has previously been shown that inhibitors of sodium–coglucose transporter 2 (SGLT2 inhibitors) may exert their beneficial effects directly on the heart via inhibition of NHE1, 4,5 as SGLT2 is not present in the heart 6 . Additionally, our working group has shown recently in that gliflozins increase myocardial expression of GLUT1, thus increasing glucose uptake into cardiomyocytes 7 while also altering myocardial sodium homoeostasis 6 . Furthermore, expression and activity of NHE1 have been shown to be affected by hypoxia and glucocorticoid levels, among others, via serum and glucocorticoid‐inducible kinase 1 (Sgk1) 8,9 .…”

Section: Introductionmentioning

confidence: 99%

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Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID‐19

et al. 2020

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Aims We aimed to assess whether expression of whole‐blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID‐19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID‐19 patients. Methods and results Whole‐blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS‐CoV‐2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID‐19 patients. NHE1 expression is up‐regulated in whole blood of patients with COVID‐19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID‐19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID‐19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID‐19 in comparison with the myocardium of non‐infected donors. Conclusions NHE1 and GLUT1 may be critically involved in the disease progression of SARS‐CoV‐2 infection. We show here that SARS‐CoV‐2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID‐19.

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“…In addition, in vitro studies using murine and human ventricular cardiomyocytes demonstrated that Empa increases the glucose transporter 1 expression and enhances glucose uptake [117].…”

Section: Cardiovascular Effect Of Sglt2imentioning

confidence: 99%

SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects

Tentolouris

Vlachakis

Tzeravini

et al. 2019

IJERPH

190

131

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Type 2 diabetes mellitus is a chronic metabolic disease associated with high cardiovascular (CV) risk. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the latest class of antidiabetic medication that inhibit the absorption of glucose from the proximal tubule of the kidney and hence cause glycosuria. Four SGLT2i are currently commercially available in many countries: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT2i reduce glycated hemoglobin by 0.5%–1.0% and have shown favorable effects on body weight, blood pressure, lipid profile, arterial stiffness and endothelial function. More importantly, SGLT2i have demonstrated impressive cardioprotective and renoprotective effects. The main mechanisms underlying their cardioprotective effects have been attributed to improvement in cardiac cell metabolism, improvement in ventricular loading conditions, inhibition of the Na+/H+ exchange in the myocardial cells, alteration in adipokines and cytokines production, as well as reduction of cardiac cells necrosis and cardiac fibrosis. The main adverse events of SGLT2i include urinary tract and genital infections, as well as euglycemic diabetic ketoacidosis. Concerns have also been raised about the association of SGLT2i with lower limb amputations, Fournier gangrene, risk of bone fractures, female breast cancer, male bladder cancer, orthostatic hypotension, and acute kidney injury.

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Empagliflozin enhances human and murine cardiomyocyte glucose uptake by increased expression of GLUT1

Cited by 18 publications

References 7 publications

Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID‐19

SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects

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Empagliflozin enhances human and murine cardiomyocyte glucose uptake by increased expression of GLUT1

Cited by 18 publications

References 7 publications

Empagliflozin inhibits Na+/H+ exchanger activity in human atrial cardiomyocytes

Empagliflozin inhibits Na+/H+ exchanger activity in human atrial cardiomyocytes

Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID‐19

SGLT2 Inhibitors: A Review of Their Antidiabetic and Cardioprotective Effects

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Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes

Empagliflozin inhibits Na⁺/H⁺ exchanger activity in human atrial cardiomyocytes