Sympathetic nervous system hyperactivity-induced oxidative stress promoting endothelial dysfunction is dependent on the NADPH oxidases/SGLT2 crosstalk: potential role in cardiogenic shock

Abstract Background Hyperactivity of the sympathetic nervous system (SNS) promotes cardiac dysfunction, that can contribute to heart failure and even cardiogenic shock. Endothelial dysfunction associated with increased formation reactive oxygen species (ROS) has been suggested promote failure. Our previous results showed SGLT2 ROS derived from endothelial NADPH oxidases dysfunction. Purpose Therefore, this study examined whether shock hyperactivation SNS involve in development using vitro vivo approaches. Methods Peripheral blood patients healthy controls was drawn by vein puncture into tubes containing sodium citrate. Cultured human microvascular cells (HMEC-1) were stimulated either 100 nM β-adrenergic agonist isoproterenol or heparinized (10 U/ml) patient plasma. Male wild-type mice lacking oxidase subunit p22phox endothelium (p22phox ecKO, 11-week-old) treated (100 mg/kg) for five consecutive days sacrificed at day 14. levels assessed dihydroethidium fluorescence, expression target genes proteins RT-qPCR Western blot, respectively. siRNA approaches used down-regulate SGLT2. Results Exposure HMEC-1 plasma suffering ROS. reduced N-acetylcysteine (an antioxidant) silencing p22phox, empagliflozin (a selective inhibitor) as well metoprolol beta1 adrenergic receptor antagonist) ICI-118,551 beta2 antagonist). Cardiogenic upregulated subunits Nox4 These responses prevented SGLT2, empagliflozin. In addition improved function blunted expression, ecKO protected against isoproterenol-induced senescence, characterized upregulation eNOS, nitrotyrosine, VCAM-1 p16 left ventricle. Conclusion hyperactivity shock-derived cause a feed forward loop between promoting pro-oxidant via activation both receptors. The oxidase/SGLT2 crosstalk also contributes hyperactivity-induced Thus, oxidases/SGLT2 appears have major role diseases such Funding Acknowledgement Type funding sources: Public hospital(s). Main source(s): Deutsches Herzzentrum München