Direct Cardiac Actions of the Sodium Glucose Co‐Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure‐Overload Heart Failure

Abstract

Background We determined if the sodium glucose co‐transporter 2 inhibitor empagliflozin attenuates pressure overload‐induced heart failure in non‐diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4–6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction‐induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate‐activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate‐activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure‐overload in non‐diabetic mellitus mice.

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

“…Several favorable effects of SGLT2 inhibitors such as increased diuresis [ 24 ], decreased arterial stiffness [ 25 ], weight and blood pressure reduction [ 1 , 26 ], and other cardiac benefits [ 27 ] contribute to positive outcomes in heart failure. The cardioprotective effects were also attributed to the modification of the cardiac metabolome and anti-oxidants [ 13 ], increased energy production from glucose, ketone bodies and fatty acid oxidation [ 10 , 28 ], anti-inflammation [ 29 ], and improved myocardial oxidative phosphorylation [ 30 ]. Moreover, empagliflozin reduced Ca 2+/ calmodulin-dependent kinase II (CaMKII)-activity and CaMKII-dependent SR Ca 2+ leak in ventricular myocytes [ 31 ].…”

Empagliflozin maintains capillarization and improves cardiac function in a murine model of left ventricular pressure overload

“…Evidence indicates that the beneficial biological effects of these drugs may be mediated by several mechanisms. For example, hemodynamic effects and increased ketone production, inhibition of sodium-hydrogen exchange in myocardial cells, enhancement of myocardial oxidative phosphorylation, and reduction of adrenergic tone were reported to be cardioprotective 6,12,[27][28][29] . The lack of knowledge about the underlying mechanisms motivated us to look for other potential pathways that may be involved; however, the search for new molecular mechanism proved to be challenging.…”

Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency, and diastolic function early in life

“…The Ca 2 þ -free buffer was replaced with Ca 2 þ -free buffer containing 0.3 mg/g body weight collagenase D (Roche; 11088858001), 0.4 mg/g body weight collagenase B (Roche; 11088807001), and 0.05 mg/g body weight protease type XIV (Sigma; P5147) dissolved in 25 mL of perfusion buffer for 3-5 min. The hearts were removed from the perfusion apparatus and minced, and then extracellular Ca 2 þ was gradually added back to the buffer starting at 0.06 mM to a final concentration of 1.2 mM with intervals of 15 min at 37 C as previously described (12,13).…”

“…Intracellular Ca 2 þ transients were determined using a dual-excitation, single-emission photomultiplier system (IonOptix). Cardiomyocytes were treated with Fura-2-acetoxymethyl ester (Fura-2AM) (2 μM) at 37 C for 20 min as previously described (12,13), and calcium baseline signal (F340/380), calcium peak signal, time to peak calcium normalized to baseline, and maximum velocity of calcium change during relaxation were measured.…”