Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction
| Autor: | Pieter Koolwijk, Diederik W. D. Kuster, Rushd Al-Shama, Etto C. Eringa, Jolanda van der Velden, Victor W.M. van Hinsbergh, Rio P. Juni, Marc G. Vervloet, Henrike M Hamer |
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| Přispěvatelé: | Fysiologie, RS: Carim - H08 Experimental atrial fibrillation, Physiology, ACS - Heart failure & arrhythmias, Laboratory Medicine, Nephrology, ACS - Diabetes & metabolism, ACS - Microcirculation |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MITOCHONDRIAL FRAGMENTATION STRESS endothelium-to-cardiomyocyte crosstalk mitochondrial oxidative damage 030232 urology & nephrology heart failure cardiomyocyte relaxation and contraction chemistry.chemical_compound 0302 clinical medicine Glucosides Myocytes Cardiac Endothelial dysfunction chemistry.chemical_classification RISK OUTCOMES Ejection fraction Endothelial stem cell PRESERVED EJECTION FRACTION Nephrology HEART-FAILURE medicine.medical_specialty empagliflozin INHIBITION RENAL DYSFUNCTION Nitric Oxide Nitric oxide 03 medical and health sciences Internal medicine medicine Empagliflozin Animals Humans Endothelium Benzhydryl Compounds Renal Insufficiency Chronic Reactive oxygen species ADVANCED GLYCATION ENDPRODUCTS NITRIC-OXIDE business.industry Endothelial Cells medicine.disease Rats 030104 developmental biology Endocrinology chemistry Heart failure Endothelium Vascular business Heart failure with preserved ejection fraction chronic kidney disease |
| Zdroj: | Juni, R P, Al-Shama, R, Kuster, D W D, van der Velden, J, Hamer, H M, Vervloet, M G, Eringa, E C, Koolwijk, P & van Hinsbergh, V W M 2021, ' Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction ', Kidney International, vol. 99, no. 5, pp. 1088-1101 . https://doi.org/10.1016/j.kint.2020.12.013 Kidney International, 99(5), 1088-1101. Elsevier Science Kidney International, 99(5), 1088-1101. Nature Publishing Group |
| ISSN: | 0085-2538 |
| DOI: | 10.1016/j.kint.2020.12.013 |
| Popis: | Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure, particularly in those with preserved ejection fraction. CKD is associated with endothelial dysfunction, however, whether CKD can induce impairment of endothelium-to-cardiomyocyte crosstalk leading to impairment of cardiomyocyte function is not known. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, reduced cardiovascular events in diabetic patients with or without CKD, suggesting its potential as a new treatment for heart failure with preserved ejection fraction. We hypothesized that uremic serum from patients with CKD would impair endothelial control of cardiomyocyte relaxation and contraction, and that empagliflozin would protect against this effect. Using a co-culture system of human cardiac microvascular endothelial cells with adult rat ventricular cardiomyocytes to measure cardiomyocyte relaxation and contraction, we showed that serum from patients with CKD impaired endothelial enhancement of cardiomyocyte function which was rescued by empagliflozin. Exposure to uremic serum reduced human cardiac microvascular endothelial cell nitric oxide bioavailability, and increased mitochondrial reactive oxygen species and 3-nitrotyrosine levels, indicating nitric oxide scavenging by reactive oxygen species. Empagliflozin attenuated uremic serum-induced generation of endothelial mitochondrial reactive oxygen species, leading to restoration of nitric oxide production and endothelium-mediated enhancement of nitric oxide levels in cardiomyocytes, an effect largely independent of sodium-hydrogen exchanger-1. Thus, empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells on cardiomyocyte function by reducing mitochondrial oxidative damage, leading to reduced reactive oxygen species accumulation and increased endothelial nitric oxide bioavailability. |
| Databáze: | OpenAIRE |
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