5 Summary and Perspective
In summary, SGLT-2i’s demonstrate prominent cardiovascular protective
effects in patients with existing HF, with and without diabetes (Ankeret al. , 2021; Packer et al. , 2020). Whereas earlier
studies focused on the direct impact of SGLT-2i’s on CMs, recent work
has also emphasised ECs as a promising therapeutic target of SGLT-2i’s
(Durante et al. , 2021; Salvatore et al. , 2021).
Preclinical studies show that SGLT-2i’s exert favorable effects against
endothelial dysfunction, including inhibiting oxidative stress and
inflammatory reactions, restoring NO bioavailability, and modulating
angiogenesis (The major findings of discussed literatures are listed in
Table 1). This property might contribute to the cardiovascular benefits
observed in patients receiving SGLT-2i’s (Figure 2).
However, there are lots of controversies concerning the mechanisms
underlying these observed endothelial effects. Species differences can
only partly explain these discrepancies, and in vivo studies
using rats and mice are vulnerable to the influence of the animals
biokinetic parameters, making it difficult to extrapolate the results to
humans (Saeidnia et al. , 2015). Moreover, the relatively limited
studies in human ECs are of high diversity in origin (micro- or macro-
circulation) and developmental stage (adult or postnatal) of the cells
(Alshnbari et al. , 2020). Further studies with CMECs are
required, considering the high prevalence and clinical relevance of
coronary microvascular dysfunction in patients with HF (Shah et
al. , 2018). Remarkably, most of these in vitro studies are
performed in static cells.
Taken together, given that endothelial dysfunction is a crucial promoter
for the development of heart failure and that SGLT-2i’s exert promising
protective effects on ECs, SGLT-2i’s have a great potential in the
treatment of cardiovascular disease. Investigations regarding the direct
endothelial effect of SGLT-2i’s are needed for a better understanding of
the mechanisms underlying these cardiovascular effects.