PB1140 - Cardioprotective effect of empagliflozin and modification of sirtuins and their non-coding RNAs regulators in patients with myocardial infarction

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

AN

Anna Nowak

MD, PhD Candidate
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
Warsaw, Mazowieckie, Poland
ZW

Zofia Wicik

Postdoctoral Researcher / Bioinformatician
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
Warsaw, Mazowieckie, Poland

Presenting Author(s)

CE

Ceren Eyileten Postula

Associate Professor
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
Warsaw, Mazowieckie, Poland

Co-Author(s)

SA

Sara Ahmadova

Research Assistant
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
Warsaw, Mazowieckie, Poland
JS

Jolanta Siller-Matula

Profe
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna,1090 Vienna, Austria
Wien, Wien, Austria
Dv

Dirk von Lewinski

Professor
Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
Graz, Steiermark, Austria
HS

Harald Sourij

Professor
Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
Graz, Steiermark, Austria
MP

Marek Postula

Professor
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
Warsaw, Mazowieckie, Poland

Background: Studies showed the direct cardio-protective effect of SGLT2 inhibitors, however the mechanism of action is still unclear. We hypothesised based on in silico analyses that cardioprotective effects of SGLT2 inhibitors are due to increased expression levels of Sirtuins and their regulator-miRNAs.

Aims: To investigate the potential cardioprotective effects of empagliflozin, an SGLT2 inhibitor, and elucidate the underlying molecular mechanisms.

Methods: In silico prediction analysis by computational approach:(I) identify and rank the most promising ncRNAs associated with sirtuin pathways and SGLT2;(II) identify the top miRNAs, which was performed by preparing gene lists of: all SIRT genes; 1st level and 2nd level SGLT2 interactors; selection of genes based on GeneOntology involved in inflammation, fibrosis, oxidative stress and hypoxia-ischemia; genes involved in MI and HF based on DisGeNet database. Followed by qRT-PCR validation analysis. Patient samples were used from the EMMY, double-blinded clinical trial (NCT03087773). Each group included 24 patients (empagliflozin=24;placebo=24),plasma was collected both at baseline and after 12-weeks of treatment; longitudinal 96 samples were used for this pilot analysis.

Results: Results of in silico analysis: 6 miRNAs that targeting the highest number of SIRT1-7 genes,SGLT2 and first-level SGLT2 interactors, namely miR-34a-5p,miR-27a-3p,miR-302a-3p,miR-146a-5p,miR-182-5p and miR-124-3p (fig.1). qRT-PCR analysis: 12-weeks of empagliflozin treatment resulted in significantly higher expression levels of miR-214, miR-34a, miR-146a, miR-182-5p and SIRT2 compared to baseline (p=0.015;p < 0.001;p < 0.001;p < 0.001;p < 0.00;p=0.005,respectively). Moreover, we found that after 12-weeks of treatment, patients taking empagliflozin had significantly higher expression of SIRT6, and significantly lower expression of miR-214 and miR-302a-3p compared to patients taking placebo (p=0.036;p=0.007;p=0.042,respectively) (fig.2).

Conclusion(s): Our in silico results for the first time predicted the interaction network between ncRNAs and HF-related genes in the context of the SGLT2-sirtuin axis. We showed that based on our prediction empagliflozin, an SGLT2 inhibitor, might exhibit cardioprotective effect via molecular mechanism of SIRT2 and SIRT6 and their ncRNA regulators.