Abstract: PO0653
Empagliflozin Restores CKD-Induced Impairment of Endothelial Regulation of Cardiomyocyte Relaxation and Contraction
Session Information
- CKD Mechanisms - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Juni, Rio Putra, Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Al-Shama, Rushd, Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Kuster, Diederik W.d., Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Van der velden, Jolanda, Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Hamer, Henrike M., Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Vervloet, Marc G., Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Eringa, Etto C., Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- Koolwijk, Pieter, Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
- van Hinsbergh, Victor, Amsterdam University Medical Centres, Amsterdam Universitair Medische Centra, Amsterdam, Noord-Holland, Netherlands
Background
Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). CKD and HF are associated with endothelial dysfunction and have been shown to benefit from a sodium-glucose co-transporter 2 inhibitor, empagliflozin. We hypothesized that uremic serum from CKD patients impairs cardiomyocyte (CM) relaxation and contraction by inducing endothelial cell dysfunction and that empagliflozin protects against this effect.
Methods
Co-culture system of human cardiac microvascular endothelial cells (CMECs) with adult rat ventricular cardiomyocytes (CMs).
Results
We showed that CMECs promote CM relaxation (return velocity, Fig. A) and contraction (sarcomere shortening, Fig. B). Serum from CKD patients impaired endothelial enhancement of CM function which was rescued by empagliflozin (Fig. A-B). Exposure to uremic serum reduced nitric oxide (NO) bioavailability in CMECs and increased mitochondrial reactive oxygen species (ROS) and 3-nitrotyrosine level, indicating NO scavenging by ROS. Empagliflozin restored endothelial enhancement of NO level in CMs by restoring endothelial NO bioavailability and reducing endothelial mitochondrial ROS, an effect that was largely independent of sodium-hydrogen exchanger-1.
Conclusion
Serum from CKD patients impairs CM relaxation and contraction through induction of endothelial dysfunction driven by an increase in mitochondrial ROS production. Empagliflozin restores the enhancement effect of CMECs on CM function by reducing mitochondrial oxidative damage, leading to reduced ROS accumulation and increased endothelial NO bioavailability.