Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes

Silvia Giannattasio; Anna Citarella; Sofia Trocchianesi; Tiziana Filardi; Susanna Morano; Andrea Lenzi; Elisabetta Ferretti; Clara Crescioli

doi:10.3389/fmolb.2022.879522

Cell-Target-Specific Anti-Inflammatory Effect of Empagliflozin: In Vitro Evidence in Human Cardiomyocytes

Front Mol Biosci. 2022 May 31:9:879522. doi: 10.3389/fmolb.2022.879522. eCollection 2022.

Authors

Silvia Giannattasio^{1

2}, Anna Citarella³, Sofia Trocchianesi⁴, Tiziana Filardi³, Susanna Morano³, Andrea Lenzi³, Elisabetta Ferretti³, Clara Crescioli¹

Affiliations

¹ Laboratory of Endocrine Research, Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
² Laboratory of Nutrigenetic and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
³ Laboratory of Oncogemics, Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
⁴ Laboratory of Molecular Medicine "Alberto Gulino" Group, Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Abstract

The antidiabetic sodium-glucose cotransporter type 2 inhibitor (SGLT2i) empagliflozin efficiently reduces heart failure (HF) hospitalization and cardiovascular death in type 2 diabetes (T2D). Empagliflozin-cardioprotection likely includes anti-inflammatory effects, regardless glucose lowering, but the underlying mechanisms remain unclear. Inflammation is a primary event in diabetic cardiomyopathy (DCM) and HF development. The interferon (IFN)γ-induced 10-kDa protein (IP-10/CXCL10), a T helper 1 (Th1)-type chemokine, promotes cardiac inflammation, fibrosis, and diseases, including DCM, ideally representing a therapeutic target. This preliminary study aims to explore whether empagliflozin directly affects Th1-challenged human cardiomyocytes, in terms of CXCL10 targeting. To this purpose, empagliflozin dose-response curves were performed in cultured human cardiomyocytes maintained within a Th1-dominant inflammatory microenvironment (IFNγ/TNFα), and CXCL10 release with the intracellular IFNγ-dependent signaling pathway (Stat-1) was investigated. To verify possible drug-cell-target specificity, the same assays were run in human skeletal muscle cells. Empagliflozin dose dependently inhibited CXCL10 secretion (IC50 = 76,14 × 10-9 M) in association with Stat-1 pathway impairment only in Th1-induced human cardiomyocytes, suggesting drug-selective cell-type-targeting. As CXCL10 plays multifaceted functions in cardiac remodeling toward HF and currently there is no effective method to prevent it, these preliminary data might be hypothesis generating to open new scenarios in the translational approach to SGLT2i-dependent cardioprotection.

Keywords: CXCL10 (IP-10); SGLT2 inhibition; cardiomyocyte; cardioprotection; empagliflozin (EMPA); inflammation.