141-OR: Cardioprotective Effect of Empagliflozin and Modification of Sirtuins and Their Noncoding RNAs Regulators in Patients with Myocardial Infarction

Introduction: Studies have demonstrated direct cardio-protective effect of SGLT2 inhibitors, but the mechanism of action is unclear. We hypothesize that cardioprotective effects of SGLT2 inhibitors are due to increased expressions of Sirtuins and their regulator-miRNAs.

Method: We conducted in silico prediction analysis using a computational approach. We identified/ranked the most promising ncRNAs associated with sirtuin pathways and SGLT2. We identified top miRNAs by preparing a gene list of all SIRT genes, 1st and 2nd level SGLT2 interactors, and genes involved in inflammation, fibrosis, oxidative stress, hypoxia-ischemia, MI and HF based on DisGeNet database. We validated our findings through qRT-PCR using selected plasma samples (empagliflozin/placebo=24/24; baseline, 26-weeks after treatment) collected from the double-blinded EMMY clinical trial (NCT03087773).

Results: Our in silico analysis identified six miRNAs; miR-34a-5p, miR-27a-3p, miR-302a-3p, miR-146a-5p, miR-182-5p and miR-124-3p, which target the highest number of SIRT1-7 genes, SGLT2 and first-level SGLT2 interactors. qRT-PCR analysis showed that after 26 weeks of treatment, patients taking empagliflozin had significantly higher expression of miR-214 (p=0,015), miR-34a (p<0,001), miR-146a (p<0,001), miR-182-5p (p<0,001) and SIRT2 (p=0,005) compared to baseline. We also found that patients taking empagliflozin had significantly higher expression of SIRT6 (p=0,036), and significantly lower expression of miR-214 (p=0,007) and miR-302a-3p (p=0,042) compared to placebo.

Conclusion: Our in silico analysis for the first time predicted the interaction network between ncRNAs and HF-related genes in the context of the SGLT2-sirtuin axis. We showed based on our prediction, empagliflozin, an SGLT2 inhibitor, can demonstrate cardioprotective effects via SIRT2 and SIRT6 and their ncRNA regulators axis.