GLUT1 is required for hyperglycemia-induced CaMKII activation

• Applicants: Professor Lars Maier; Privatdozent Dr. Julian Mustroph
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546575044

Overexpression and activation of Ca/Calmodulin-dependent kinase II (CaMKII) are hallmarks of heart failure with reduced or preserved ejection fraction (HFrEF and HFpEF). CaMKII inhibitors have thus far not been translated into the clinic due to off-target toxicity or modest efficacy, which may be in part due to the non-canonical modes of CaMKII activation via oxidation or O-GlcNAcylation. Interestingly, it has been shown that not only diabetes can acutely and profoundly induce CaMKII-activation via O-GlcNAcylation, but also acute hyperglycemia without diabetes. In preliminary data for this grant application, we identified the glucose transporter 1 (GLUT1) as the primary transporter able to induce CaMKII activation and proarrhythmogenic CaMKII-dependent cardiac late sodium current (late INa) upon acute hyperglycemia. We propose that pharmacological inhibition of GLUT1 or cardiac GLUT1 knock out can abolish hyperglycemic CaMKII activation and its detrimental effects on arrhythmogenesis and contractile function. Furthermore, we propose based on extensive preliminary data that CaMKII inhibition, independent of left ventricular function, is closely linked to an induction of cardiac GLUT1 expression, which may paradoxically predispose to hyperglycemic induction of proarrhythmogenic late INa. We further provide evidence that empagliflozin exposure of cardiomyocytes shares features of CaMKII inhibition, leading to an inhibition of CaMKII-dependent late INa, inhibition of CaMKII itself, but also induction of GLUT1 expression levels. We propose that empagliflozin in contrast to CaMKII inhibitors differentially modulates GLUT1-dependent glucose levels acutely. In an ambitious but well-prepared work program we aim to determine the interaction of cardiac GLUT1 and CaMKII activity in healthy human and murine cardiomyocytes, but also in human cardiomyocytes from patients with HFrEF and a murine model of heart failure via transverse aortic constriction. We will thoroughly investigate the effects of CaMKII inhibition on cardiac glucose homeostasis, especially during conditions of acute hyperglycemia. In an innovative translational approach, we will also investigate the effects of empagliflozin on human cardiomyocyte CaMKII activity and GLUT1-dependent glucose uptake, utilizing human cardiomyocytes from patient biopsies upon in vivo treatment with empagliflozin.

• DFG Programme: Research Grants