Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis

Li, Xiaoling; Wang, Mengnan; Kalina, Jan-Ole; Preckel, Benedikt; Hollmann, Markus W.; Albrecht, Martin; Zuurbier, Coert J.; Weber, Nina C.

doi:10.1016/j.redox.2023.102979

Redox Biology

2024

DOI: 10.1016/j.redox.2023.102979

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Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis

Xiaoling Li,

Mengnan Wang,

Jan-Ole Kalina

et al.

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2024

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Cited by 4 publications

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Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Chen,

Wang,

Bakker

et al. 2024

Basic Res Cardiol

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Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

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Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Chen,

Wang,

Bakker

et al. 2024

Basic Res Cardiol

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Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review

Madonna,

Biondi,

Alberti

et al. 2024

Biomedicine & Pharmacotherapy

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Empagliflozin mitigates ponatinib-induced cardiotoxicity by restoring the connexin 43-autophagy pathway

Mattii,

Moscato,

Ippolito

et al. 2024

Biomedicine & Pharmacotherapy

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Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis

Cited by 4 publications

References 39 publications

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review

Empagliflozin mitigates ponatinib-induced cardiotoxicity by restoring the connexin 43-autophagy pathway

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