Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

Figures

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  Figure 1. Dysregulated ion homeostasis in failing cardiomyocytes. Increased late INa as well as increased forward mode NCX (constituting ITi), NHE1- and SGLT1 activity contribute to cellular Na+ overload ([Na+]i). Na+ overload, in turn, promotes cytosolic Ca2+ overload ([Ca2+]i) and mitochondrial Ca2+ depletion ([Ca2+]m) (with increased ROS generation), both of which are able to activate CaMKII, which is centrally involved in the regulation of multiple Na+ and Ca2+ channels/transporters. The solid grey lines indicate known CaMKII phosphorylation targets. NKA, Na+/K+ ATPase; RyR2, ryanodine receptor 2; SR, sarcoplasmic reticulum; NCX, Na+/Ca2+ exchanger; NCLX, mitochondrial Na+/Ca2+ exchanger; ROS, reactive oxygen species.

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  Figure 2. Beneficial effects of SGLT2i on cellular ion homeostasis. SGLT2i directly or indirectly inhibit NHE1, late INa, and CaMKII, leading to a reduction in cellular Na+ and Ca2+ overload. As a consequence of reduced [Na+] and possibly also because of direct mitochondrial effects of SGLT2i, mitochondrial ROS generation is decreased. Dashed grey lines indicate potentially reduced interaction of CaMKII with its known targets. Solid green lines indicate inhibition mediated by SGLT2i. NKA, Na+/K+ ATPase; RyR2, ryanodine receptor 2; SR, sarcoplasmic reticulum; NCX, Na+/Ca2+ exchanger; NCLX, mitochondrial Na+/Ca2+ exchanger; ROS, reactive oxygen species.

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  Figure 3. Overview of potential SGLT2i targets relevant for ion homeostasis in the heart. SGLT2i directly reduces (via inhibition of Late INa, NHE1 and potentially SGLT1) intracellular Na+ accumulation in the failing heart. Decreased [Na+]i in turn improves mitochondrial function (see Section 4.1) and thus may contribute to the decrease in mitochondrial ROS formation observed with SGLT2i treatment. Reduction of oxidative stress attenuates oxidative CaMKII activation, which, together with decreased [Na+]i, improves cellular Ca2+ handling and leads to improved diastolic and systolic function. Moreover, both restoration of Ca2+ homeostasis and CaMKII inhibition are antiarrhythmic. Downward-pointing arrows denote reduction or inhibition of a signaling pathway. Upward-pointing arrows denote stimulation or enhancement of a pathway. NHE1, Na+/H+ exchanger 1; SGLT1, sodium-glucose co-transporter 1; ROS, reactive oxygen species; CaMKII, Ca2+/calmodulin-dependent protein kinase II; [Na+]i, cytosolic Na+ concentration.