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).