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).