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.
Highlights
Cardiovascular diseases are the leading cause of death and disability around the world, especially in patients with diabetes [1]
10% stretch increased reactive oxygen species (ROS) production 2.39 ± 0.95 fold, 1 μM EMPA, 1 μM DAPA and 3 μM CANA significantly reduced the 10% stretch-induced ROS production (x-fold compared to 5% stretch, EMPA: 1.55 ± 0.98, DAPA: 1.41 ± 0.77, CANA: 1.80 ± 0.87, p all
± 0.36, p > 0.05, Figure 3c), suggesting that the protective effect of EMPA might be mediofated did not further reduce the increased cell permeability of human coronary artery endothelial cells (HCAECs) through exposed to 10% stretch
Summary
Cardiovascular diseases are the leading cause of death and disability around the world, especially in patients with diabetes [1]. Clinical trials showed that sodium glucose co-transporter 2 inhibitors (SGLT-2i’s), a class of novel glucose lowering agents, improve cardiovascular outcomes in diabetic [2,3] and non-diabetic patients [4]. One contributing mechanism could be the direct endothelial protective effect of SGLT-2i’s. Endothelial dysfunction plays a pivotal role in the progression of heart failure (HF). ROS production within endothelial cells limits nitric oxide (NO) bioavailability for adjacent cardiac myocytes and decreases protein kinase G activity, which favours cardiac hypertrophy via hypophosphorylation of titin [5].
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