Giannattasio Silvia, Citarella Anna, Trocchianesi Sofia, Filardi Tiziana, Morano Susanna, Lenzi Andrea, Ferretti Elisabetta, Crescioli Clara
Laboratory of Endocrine Research, Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
Laboratory of Nutrigenetic and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Front Mol Biosci. 2022 May 31;9:879522. doi: 10.3389/fmolb.2022.879522. eCollection 2022.
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.
抗糖尿病的钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）恩格列净可有效降低2型糖尿病（T2D）患者的心力衰竭（HF）住院率和心血管死亡风险。恩格列净的心脏保护作用可能包括抗炎作用，与血糖降低无关，但其潜在机制尚不清楚。炎症是糖尿病性心肌病（DCM）和HF发生发展的主要事件。干扰素（IFN）γ诱导的10 kDa蛋白（IP-10/CXCL10）是一种辅助性T细胞1（Th1）型趋化因子，可促进心脏炎症、纤维化及包括DCM在内的疾病，是理想的治疗靶点。本初步研究旨在探讨恩格列净是否通过靶向CXCL10直接影响受到Th1刺激的人心脏细胞。为此，在维持于Th1主导的炎症微环境（IFNγ/TNFα）中的培养人心脏细胞中进行了恩格列净剂量反应曲线实验，并研究了CXCL10释放及细胞内IFNγ依赖性信号通路（Stat-1）。为验证可能的药物-细胞靶点特异性，在人骨骼肌细胞中进行了相同实验。恩格列净仅在Th1诱导的人心脏细胞中呈剂量依赖性抑制CXCL10分泌（IC50 = 76.14×10-9 M），并伴有Stat-1通路损伤，提示药物具有选择性细胞类型靶向作用。由于CXCL10在心脏向HF重塑过程中发挥多方面作用，且目前尚无有效方法预防，这些初步数据可能为SGLT2i依赖性心脏保护的转化研究开辟新的思路。
