1.2 Anti-oxidative effect of SGLT-2i’s
Mounting evidence reveals a class effect of ROS inhibition for SGLT-2i’s. In vivo studies showed that ipragliflozin decreased urinary 8-hydroxy-2′-deoxyguanosine (a marker for DNA oxidative injury) in hyperglycaemic mice (Salim et al. , 2016), and dapagliflozin (DAPA) attenuated elevated vascular ROS generation in aortic atherosclerotic tissues of diabetic mice (Leng et al. , 2016). However, it might be considered that these observed ROS inhibitory effects of SGLT-2i’s were mediated by the decreased blood glucose in mice with diabetes.
Live cell imaging suggested that SGLT-2i’s directly inhibited inflammation-stimulated ROS production within human ECs from both venous and arterial vessels (Uthman et al. , 2019). Two other studies showed that EMPA reduced ROS production within cardiac microvascular endothelial cells (CMECs) exposed to pro-inflammatory cytokines and uremic acid (Juni et al. , 2019; Juni et al. , 2021). By preventing ROS accumulation within ECs, EMPA restored NO bioavailability in co-cultured CMs, indicating that the ROS inhibitory capacity of SGLT-2i’s contributes to the improvement of contraction and relaxation of adjacent CMs through an endothelial-NO pathway (Juni et al. , 2019; Juni et al. , 2021). A more recent study reported a novel ROS inhibitory effect of SGLT-2i’s in human coronary artery endothelial cells (HCAECs) undergoing enhanced cyclic stretch, suggesting that SGLT-2i’s might also alleviate oxidative stress caused by mechanical forces (Li et al. , 2021). This study firstly showed that SGLT-2i’s prevented the loss of VE-cadherin and alleviated barrier dysfunction in HCAECs undergoing enhanced stretch, which was mediated by their ROS inhibitory effect (Li et al. , 2021).