Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

Abstract

SGLT-2i’s exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i’s empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i’s (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i’s improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i’s might be partially mediated by inhibition of NHE1 and NOXs.

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

“…The inhibition of the sodiumhydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) attenuated the stretchinduced ROS production but did not produce a further ROS reduction when combined with empagliflozin. These results seem to indicate that the protection of human endothelial cells by gliflozins is most likely mediated through an anti-oxidative effect that only partially depends on the inhibition of NHE1 and NOXs [97].…”

The Role of Sodium Glucose Cotransporter-2 Inhibitors in Atherosclerotic Cardiovascular Disease: A Narrative Review of Potential Mechanisms

“…Empagliflozin has also been demonstrated to prevent cell death in HUVEC's exposed to hypoxic stress in culture and reduce infarct size after ischaemia/reperfusion injury in mice, suggesting SGLT2 inhibitors reduce the impact of oxidative stress [72]. In vitro studies of antioxidant effect of SGLT2 inhibitors on human coronary artery endothelial cells (HCAEC's) similarly demonstrated reduced cell permeability and reactive oxygen species production compared to control [73]. Clinical studies assessing flow mediated dilatation (FMD) of the brachial artery, a surrogate for endothelial dysfunction in coronary arteries and systemically [23], demonstrated improved changes in FMD from baseline with SGLT2 inhibitors compared to metformin at 16 weeks in those with early stage diabetes [74].…”

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…This important feature of SGLT2i is linked to their impact on redox signaling in AF, and this has recently been comprehensively reviewed [133]. SGLT2i also exerts direct antiinflammatory and anti-oxidative effects on resting endothelial cells, and its anti-oxidative effect could be partly mediated by NADPH oxidase inhibition [134]. Moreover, chronic SGLTi treatment has been shown to protect diabetic mice from inflammation [135].…”