TY - JOUR
T1 - Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction
AU - Juni, Rio P
AU - Al-Shama, Rushd
AU - Kuster, Diederik W D
AU - van der Velden, Jolanda
AU - Hamer, Henrike M
AU - Vervloet, Marc G
AU - Eringa, Etto C
AU - Koolwijk, Pieter
AU - van Hinsbergh, Victor W M
N1 - Funding Information: The authors acknowledge Max Goebel, Valentijn Jansen, and Michiel van Wijhe for the excellent technical assistance. The authors also acknowledge the support of CVON RECONNECT from the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, and Royal Netherlands Academy of Science). RPJ, PK, and VWMvH designed the study. RPJ and RA-S carried out the experiments. MGV and HMH provided samples and clinical data from patients with chronic kidney disease. RPJ and RA-S analyzed the data. RPJ made the figures. RPJ drafted the manuscript. RPJ, DWDK, JvdV, HMH, MGV, ECE, PK, and VWMvH revised the manuscript. All authors approved the final version of the manuscript. Publisher Copyright: © 2020 International Society of Nephrology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - cardiomyocyte relaxation and contraction
KW - chronic kidney disease
KW - empagliflozin
KW - endothelium-to-cardiomyocyte crosstalk
KW - heart failure
KW - mitochondrial oxidative damage
UR - http://www.scopus.com/inward/record.url?scp=85102886806&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.kint.2020.12.013
DO - https://doi.org/10.1016/j.kint.2020.12.013
M3 - Article
C2 - 33359500
SN - 0085-2538
VL - 99
SP - 1088
EP - 1101
JO - Kidney International
JF - Kidney International
IS - 5
ER -