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.