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Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor
Koenraad Philippaert1,2, Subha Kalyaanamoorthy3,4, Mohammad Fatehi1,2
1Alberta Diabetes Institute (K.P., M.F., W.L., A.B., J.S., J.W., T.P., C.S., J.M.S., P.E.L.), University of Alberta, Edmonton, Canada.xs.
Background:
SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa.
Methods:
Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.
Results:
The SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa 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 three-dimensional 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 anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia.
Conclusions:
Our results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the late sodium current (late-INa) in heart failure models. This finding suggests SGLT2 inhibitors may offer cardioprotection by targeting this cardiac sodium channel current.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrate significant cardioprotective effects in diabetic patients with heart failure.
- The precise molecular mechanisms underlying these cardioprotective effects remain under investigation.
- The late component of the cardiac sodium channel current (late-INa) is implicated in the pathophysiology of heart failure.
Purpose of the Study:
- To investigate whether SGLT2 inhibitors can inhibit the late component of the cardiac sodium channel current (late-INa).
- To explore the potential molecular mechanisms by which SGLT2 inhibitors exert cardioprotection.
Main Methods:
- Electrophysiological studies in cardiomyocytes.
- In silico molecular docking simulations.
- Calcium imaging and whole-heart perfusion techniques.
Main Results:
- Empagliflozin, an SGLT2 inhibitor, significantly reduced late-INa in mouse cardiomyocytes and in Nav1.5 channels with specific mutations.
- Empagliflozin, dapagliflozin, and canagliflozin selectively inhibited H2O2-induced late-INa without affecting peak sodium current.
- Empagliflozin binding to Nav1.5 occurs in a similar region to local anesthetics and ranolazine, and it prevented inflammasome activation and improved cardiac function post-ischemia.
Conclusions:
- Late-INa represents a potential molecular target for SGLT2 inhibitors in the heart.
- Inhibition of late-INa may contribute to the cardioprotective effects of SGLT2 inhibitors.
- These findings elucidate a novel mechanism for SGLT2 inhibitor-mediated cardioprotection.
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