2.2 Anti-inflammatory capacity of SGLT-2i’s
A recent clinical trial revealed that 24-week treatment with EMPA
significantly reduced serum ICAM-1 level and prevented
leukocyte-endothelium interactions in patients with DM (Canet et
al. , 2021). EMPA inhibited macrophage accumulation, as well the
expression of monocyte chemoattractant protein-1 and ICAM-1 in the
aortic arch of diabetic mice (Ganbaatar et al. , 2020) and DAPA
attenuated the high-salt diet-induced upregulation of VCAM-1 in
euglycaemic rats and lowered NF-κB expression within rat ECs (Cappettaet al. , 2020). Another study showed that EMPA limited Ang
II-induced abdominal aortic aneurysm in ApoE knockout mice, partially
through inhibiting activation of p38 MAPK and NF-κB in aortas, as well
reducing macrophage infiltration within lesions (Ortega et al. ,
2019).
Consistently, in vitro studies revealed that DAPA attenuated the
increased ICAM-1 and VCAM-1 secretion of HUVECs exposed to
hyperglycaemia or TNF-α for 24 h (Gaspari et al. , 2018) and that
EMPA inhibited the TNF-α triggered leukocyte adhesion towards human ECs
cultured under flow (Cooper et al. , 2019). However, the
anti-inflammatory effect in Cooper’s study was achieved by very with
high concentration of EMPA (50 µM) (Cooper et al. , 2019). Uthman
et al. reported a neutral effect of EMPA (1 µM) on TNF-α-induced
adhesion molecules expression in static human ECs (Uthman et al. ,
2019). In the latter study, ICAM-1 and VCAM-1 were measured 4 h after
TNF-α stimulation with flow cytometry, instead of using the supernatant
of cell culture as in the study of Gaspari et al. (Uthman et al. ,
2019; Gaspari et al. , 2018). The dosage of SGLT-2i’s also
differed in these two study (1 µM vs. 1-5 nM, respectively). Yet, lower
doses of DAPA (1 and 10 nM) did not inhibit expression of adhesion
molecules either in the study of Uthman et al (Uthman et al. ,
2019). Additionally, static cells are not directly comparable to cells
cultured under flow. Static cells develop a thinner glycocalyx (GCX)
layer than dynamically activated ECs, and the latter model is considered
more physiologically relevant because in situ endothelial cells
are constantly exposed to mechanical forces generated by blood flow
(Chistiakov et al. , 2017; Haymet et al. , 2021).
Uthman et al. recently reported a compound-specific effect of
canagliflozin (CANA) in inhibiting IL-6 secretion by HCAECs exposed to
lipopolysaccharide (Uthman et al. , 2020). In this study, only
CANA activated adenosine monophosphate-activated protein kinase (AMPK),
while EMPA or DAPA did not alter AMPK phosphorylation in HCAECs (Uthmanet al. , 2020). The different impact on AMPK might partially
explain the diverse effects of the three SGLT-2i’s on vascular
inflammation. Moreover, CANA-induced IL-6 reduction was significantly
diminished after glycolytic hexokinase II (HKII) knockdown, revealing a
novel anti-inflammatory mechanism of CANA via inhibiting glycolysis
(Uthman et al. , 2020).