4.2 The effect of SGLT-2i’s on angiogenesis
The effect of SGLT-2i’s on angiogenesis is still controversial.
Previously, Zhou et al. demonstrated that EMPA promoted angiogenesis of
CMECs in diabetic mice, thus improving myocardial microcirculatory
perfusion and cardiac function (Zhou et al. , 2018). This study
showed that EMPA preserved angiogenetic capacity of isolated CMECs
through stabilization of F-actin. The effect of EMPA was nearly
abolished when EMPA was combined with FCCP, a mitochondrial fission
activator to promote mtROS generation (Zhou et al. , 2018).
Excessive ROS arrested the cell cycle transition from G0/G1 to S and
interrupted CMECs proliferation, which was re-established by EMPA and
mdivi1 (an inhibitor for mitochondrial fission) (Zhou et al. ,
2018). Taken together, prevention of mitochondrial fission and
subsequent oxidative stress by EMPA was involved in its pro-angiogenetic
effects on CMECs. Correspondingly, a recent study from Nikolaou et al.
showed that chronic administration (6 weeks) of EMPA reduced myocardial
infarct size after ischemia-reperfusion in non-diabetic mice, and this
cardioprotective effect of EMPA could be partially explained by the
improved CMECs survival (Nikolaou et al. , 2021). An in
vitro study with human ECs exposed to hypoxia/reoxygenation stress also
proved that EMPA increased cellular viability via activating signal
transducer and activator of transcription 3 pathway (Nikolaou et
al. , 2021). Using human aortic endothelial cells (HAECs), another study
revealed that the autophagy is also involved in the pro-angiogenic
effect of EMPA. The anti-leukemia agent ponatinib (PON) induces
vasculotoxicity via mitochondrial damage, while the autophagy-mediated
removal of injured mitochondria represents a cardiovascular protective
mechanism against the toxic insult of PON. HAECs exposed to PON showed
decreases in autophagy marker expression (LC3-I/II), tube formation as
well cell viability, which were reverted by EMPA (Madonna et al. ,
2021).
In contrast, Behnammanesh et al. reported a robust anti-proliferative
and anti-migration effect of CANA in HUVECs and HAECs (Behnammaneshet al. , 2019). In clinically relevant dosages, CANA (5 µM and 10
µM) inhibited the proliferation of HUVECs by reducing the expression of
cyclin A, as well as by reducing phosphorylation of the retinoblastoma
protein, while EMPA and DAPA barely influenced the proliferative
capacity of ECs in their physiological dosage (1-2 µM) (Behnammaneshet al. , 2019; Devineni et al. , 2016; Tomlinson et
al. , 2017). The anti-proliferative effect of CANA could also be
beneficial: CANA suppressed the increased proliferation and tubular
formation of HUVECs during co-culture with Huh7 and HepG2
(hepatocyte-derived carcinoma cell lines), as well the enhanced
production of angiogenic cytokines (e.g. IL-8), thus inhibiting the
growth of liver cancer (Kaji et al. , 2018). More recently,
another study showed that CANA had a dosage-dependent inhibitory effect
on the VEGF-A expression and angiogenesis of HUVECs co-cultured with
HepG2 cell line (Luo et al. , 2021).
Several factors might explain the observed opposite effects of CANA and
EMPA on angiogenesis. Firstly, these studies were performed with ECs
under different “stress” conditions. Cells in the EMPA studies were
activated with pathological stimuli (diabetes, hypoxia/reoxygenation and
PON) that impaired their cellular viability and angiogenesis capacity
(Zhou et al. , 2018; Nikolaou et al. , 2021; Madonnaet al. , 2021), while the anti-angiogenic effect of CANA was
reported in “non-stimulated” cells or ECs co-cultured with cancer
cells (Behnammanesh et al. , 2019; Kaji et al. , 2018; Luoet al. , 2021). The potential involvement of SGLT-1 is also of
importance, considering that anti-proliferating effect seems to be
compound-specific for CANA (Behnammanesh et al. , 2019). Compared
with EMPA and DAPA, CANA is relatively less selective for SGLT-2 over
SGLT-1, and the latter is highly expressed in human ECs (Ohgaki et
al. , 2016). However, in a HepG2 and ECs co-culture model, CANA reduced
glucose uptake and growth of liver cancer cells via inhibiting SGLT-2
rather than SGLT-1 (Kaji et al. , 2018). Moreover, the effect of
SGLT-2i’s on ECs proliferation and migration might vary among different
organs/tissues, and more research is required to explain these existing
differences.