Dapagliflozin Prevents ERK Activation and SGLT2-Dependent CD105 Upregulation in Mechanically-stretched Cardiomyocytes
Research Square (Research Square)(2022)
Abstract
Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI). AMI is one of the long-term effects for heart failure and its underlying mechanism is not well-understood. In this study, we aimed to investigate the role of SGLT2 when cardiac cells were subjected to mechanical cyclic stretch. We hypothesized that SGLT2 is required for sensing mechanical stretch in cardiomyocytes. Method Human cardiomyocytes were cultured as monolayer on stretchable membranes, subjected to cyclic stretch for 24h at 1 Hertz (Hz). The TGFB1 or CD105 were used as specific biomarker for AMI in cardiomyocytes. Results AMI (+) serum showed increased TGFB1 and CD105 compared to AMI (-) patients. In consistent, Troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were up-regulated after 5% and 25% of 24h cyclic stretch. SGLT2 inhibition through Dapagliflozin addition significantly decreased Troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. Conclusion This discovery of CD105 and SGLT2 increase in mechanically-stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model.
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Key words
dapagliflozin prevents erk activation,cardiomyocytes,mechanically-stretched
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