Effects of SGLT2 inhibitors on ion channels in heart failure: focus on the endothelium

Abstract

Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca²⁺ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca²⁺ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca²⁺-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.

Keywords: Endothelial cells; Endothelial dysfunction; Heart failure; Ion channels; Sodium-glucose cotransporter 2 inhibitors; Vascular tone.

Fig. 1

The mechanism of SGLT2i underlying HF. SGLT2i improve cardiac preload and afterload through their diuretic effect and inhibitory effect on SNS as well as RAAS. Furthermore, SGLT2i exert direct cardioprotective effects by enhancing NO bioavailability, reducing ROS generation and inhibiting cardiac NHE1 activity. SGLT2i sodium-glucose transporter inhibitors, SNS sympathetic nervous system, RAAS renin–angiotensin–aldosterone system, NOS nitric oxide synthase, ROS reactive oxygen species, NHE sodium-hydrogen exchanger

Fig. 2

The role of endothelial ion channels in HF. ECs express many ion channels modulating ion homeostasis and are involved in several signaling transduction pathways. Healthy ECs secrete NO and EDHF to regulate vascular tone (left). Piezo-1 activates TRPV4 mediating the upregulation of [Ca²⁺]_i. Increased [Ca²⁺]_i stimulates IK_Ca and SK_Ca in ECs to generate EDH which spreads to adjacent SMC via MEGJs, leading to vascular relaxation. In addition, NO diffuses to SMC activating cGMP, resulting in vasodilation. In the failing heart (right), changes in endothelial ion channels disrupt ion homeostasis. The activation of NHE increases [Na⁺]_i which triggers the reverse mode of NCX, leading to Ca²⁺ overload. Ca²⁺ overload inhibits IK_Ca and SK_Ca in ECs while promoting ROS generation. ROS overproduction deteriorates NO bioavailability, resulting in vasoconstriction. EDH endothelium-dependent hyperpolarization; [Ca²⁺]_i: intracellular calcium concentration; Ca_V voltage-gated Ca²⁺ channels; K_V voltage-gated K⁺ channel; NHE Na⁺/H⁺ exchanger; NCX Na⁺/Ca²⁺ exchanger; I_NaL late sodium current; MEGJs myoendothelial gap junctions; SK_Ca small Ca²⁺-activated K⁺ channels; IK_Ca intermediate conductance Ca²⁺-activated K⁺ channels

Fig. 3

The effects of SGLT2i on endothelial ion channels. SGLT2i decrease intracellular Na⁺ and Ca²⁺ overload by directly or indirectly inhibiting NHE1 and NCX. A reduction in Ca²⁺ inhibits ROS generation. In addition, SGLT2i alleviate endothelial inflammation as well as impaired eNOS activity, which might be through the NHE1 inhibition and AMPK activation. NHE Na⁺/H⁺ exchanger; NCX Na⁺/Ca²⁺ exchanger; mNCX mitochondria Na⁺/Ca²⁺ exchanger; ROS reactive oxygen species; AMPK AMP-activated protein kinase