Background:
Sodium/glucose co-transporter 2 (SGLT2) inhibitors exert robust cardioprotective effects against heart failure in diabetes patients and there is intense interest to identify the underlying molecular mechanisms that afford this protection. As the induction of the late component of the cardiac sodium channel current (late-I
Na
) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-I
Na
.
Methods:
Electrophysiological, in silico molecular docking, molecular, calcium imaging and whole heart perfusion techniques were employed to address this question.
Results:
The SGLT2 inhibitor empagliflozin reduced late-I
Na
in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the LQT3 mutations R1623Q or ∆KPQ. Empagliflozin, dapagliflozin and canagliflozin are all potent and selective inhibitors of H
2
O
2
-induced late-I
Na
(IC
50s
= 0.79, 0.58 and 1.26 µM respectively) with little effect on peak-I
Na
. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-I
Na
activator veratridine in a similar manner to tetrodotoxin, ranolazine and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a 3D homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anaesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 inflammasome and improved functional recovery after ischemia.
Conclusions:
Our results provide evidence that late-I
Na
may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin
