SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Abstract

Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

Keywords: NHE; SGLT2; fission; fusion; ketone body; mitochondria.

Copyright © 2020 Maejima.

Figures

Figure 1

(A) Physiology of glucose reabsorption in the renal proximal tubules and the target of SGLT2 inhibitors. GLUT, glucose transporter; KCNE1, potassium voltage-gated channel Isk-related family member 1; KCNQ1, potassium voltage-gated channel KQT-like subfamily member 1; NHE, Na+/H+ exchanger; NKA, Na+/K+ ATPase; SGLT, sodium-dependent glucose transporter. (B) Chemical structural formulas of Phlorizin and SGLT2 inhibitors (Dapagliflozin, Empagliflozin, Canagliflozin, Ipragliflozin, Tofogliflozin, and Luseogliflozin).

Figure 2

SGLT2 inhibitors increase the amount of ketone bodies, thereby promoting cardioprotective effects. The inhibition of SGLT2 reduces plasma glucose levels, thereby promoting lipolysis in adipose tissue, which in turn enhances the generation of ketone bodies. On the other hand, a growing body of evidence suggests that ketone bodies are favorable substrates in energy production because the conversion of ketone bodies to acetyl-CoA is much easier in comparison to the conversion of FFAs and glucose to acetyl-CoA. Furthermore, transcriptional level changes of ketone oxidation-related genes would be associated with the substrate shift to ketone bodies in the failing heart. Both pink and blue arrows show the changes in heart failure. AcAc CoA, Acetoacetyl CoA; ACAT1, Acetyl-CoA acetyltransferase; ADP, Adenosine diphosphate; ATP, Adenosine triphosphate; BDH1, Mitochondrial β-hydroxybutyrate dehydrogenase; βOHB, β-hydroxybutyrate; βOHB CoA, β-hydroxybutyryl CoA; C2-carnitine, Acetylcarnitine; C4-OH carnitine, Hydroxybutyrylcarnitine; CPT1, Carnitine palmitoyltransferase 1; ETC, Electron transport chain; HMGCL, 3-hydroxy-3-methylglutaryl-coenzyme A lyase; HMGCS2, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2; and SCOT, Succinyl-CoA:3-oxoacid-CoA transferase.

Figure 3

SGLT2 inhibitors promote sodium metabolism-mediated cardioprotective effects. Failing cardiomyocytes show elevated intracellular Na+ concentrations due to (1) increased Na+ influx via the late Na+ current (INa), (2) enhanced sarcolemmal Na+/H+ exchanger (NHE) activity, (3) reduced Na+/K+ ATPase (NKA) activity, and in the case of the diabetic heart, (4) the increased expression and activity of Na+-glucose cotransporter 1 (SGLT1). Intracellular overload of Na+ promotes Ca2+ efflux from mitochondria through the mitochondrial Na+/Ca2+ exchanger (NCLX). The reduction of the Ca2+ concentration in the mitochondrial matrix deteriorates the Ca2+-induced upregulation of TCA cycle dehydrogenases in response to workload transition, thereby disturbing the regeneration of reducing equivalents that are essential for preserving the antioxidative capacity and matching the energy supply to the energy demand. SGLT2 inhibitors would have a salutary role in failing cardiomyocytes through their alleviation of Na+ and Ca2+ handling through NHE inhibition. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ETC, electron transport chain; MCU, mitochondrial Ca2+ uniporter; NAD+/NADH, nicotine amide dinucleotide oxidized/reduced; NCX, sarcolemmal Na+/Ca2+ exchanger; NKA, Na+/K+ ATPase; RyR, ryanodine receptor; SERCA, sarcoplasmic reticulum Ca2+ ATPase.

Figure 4

Hypothesized mechanism of the modulation of mitochondrial dynamics by SGLT2 inhibitors. The inhibition of SGLT2 might be associated with the mitochondrial dynamics through the regulation of (A) mitochondrial fusion and (B) mitochondrial fission. However, the detailed mechanism as to how SGLT2 inhibitors modulate the regulators of mitochondrial dynamics is largely unknown. AMPK, AMP-activated protein kinase; Drp1, Dynamin-related protein 1; Fis1, Mitochondrial fission 1 protein; Mfn, Mitofusin; Ser, Serine.