Hydrogen sulphide as a potential contributer to cardiovascular protection with sodium-glucose cotransporter 2 inhibition

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), developed for the treatment of diabetes mellitus, exert remarkable cardiovascular benefits beyond glycaemic control. The underlying mechanism of this pluripotent protection is heterogeneous and involves interactions with a number of haemodynamic, metabolic and cellular signalling pathways. Emerging findings demonstrate that a natural gaseous product of arterial wall, H₂S, participates in a number of physiological reactions, and its deficiency is associated with cardiovascular pathologies, such as arterial hypertension, heart failure and chronic kidney disease. Recent experimental observations have suggested the possibility of a functional link between SGLT2i and H₂S signalling in the context of cardiovascular protection. Emerging data suggest that SGLT2i- and H₂S-dependent pathways may overlap or complement each other in protective mechanisms. Several plausible areas of interaction between SGLT2i and H₂S have recently emerged. Both agents stimulate PI3K/Akt/eNOS signalling, thereby increasing the bioavailability of NO with beneficial vasodilatory and antiproliferative effects. SGLT2i and H₂S also favourably regulate the redox state through inhibition of NADPH oxidase, thus protecting subcellular structures. Moreover, both SGLT2i and H₂S appear to affect autophagy and improve mitochondrial function through AMPK and sirtuin signalling, thus contributing to the restoration of physiological substrate processing pathways and cellular energy balance. In addition, both SGLT2i and H₂S supposedly downregulate the Na⁺/H⁺ exchanger, normalize the Fe²⁺ cytosolic level in cardiomyocytes and promote erythropoietin release, actions that could improve the metabolism and function of cardiovascular organs. Elucidating the nature of possible crosstalk between H₂S, delivered by endogenous stimulation or exogenous supplementation, and SGLT2i may desirably modify the approach to the treatment of cardiovascular diseases and represents a challenging research topic.