Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, New York (P.M., A.L., U.K., F.V., S.S.J., G.S.); Azienda Sanitaria Locale (ASL) Avellino, Avellino, Italy (P.M., A.P., S.D.G., M.F., G.M., S.F.); University of Salerno, Fisciano, Italy (S.M.); International Translational Research and Medical Education Consortium (ITME) and Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (G.S.); and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, New York City, New York (U.K., F.V., S.S.J., G.S.)
Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, New York (P.M., A.L., U.K., F.V., S.S.J., G.S.); Azienda Sanitaria Locale (ASL) Avellino, Avellino, Italy (P.M., A.P., S.D.G., M.F., G.M., S.F.); University of Salerno, Fisciano, Italy (S.M.); International Translational Research and Medical Education Consortium (ITME) and Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (G.S.); and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Albert Einstein College of Medicine, New York City, New York (U.K., F.V., S.S.J., G.S.).
J Pharmacol Exp Ther. 2023 Jan;384(1):116-122. doi: 10.1124/jpet.121.001251. Epub 2022 Jul 25.
Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in a population of frail older adults with HFpEF and DM treated for 3 months with empagliflozin, metformin, or insulin. We identified a distinctive pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and to HFpEF patients treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin, whereas no significant differences in the profile of endothelial miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs involved in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to SGLT2 inhibition. SIGNIFICANCE STATEMENT: We have identified a novel microRNA signature functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. Moreover, the treatment with the SGLT2 inhibitor empagliflozin caused a modification of some of these microRNAs in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant for clinical practice inasmuch as we were able to establish novel biomarkers of disease and response to therapy.
内皮功能障碍是射血分数保留型心力衰竭（HFpEF）、糖尿病（DM）和虚弱的关键机制。然而，缺乏监测这些患者内皮功能障碍的可靠生物标志物。在这项研究中，我们评估了一组循环 microRNAs（miRs）在 HFpEF 和 DM 患者中的表达，这些患者接受恩格列净、二甲双胍或胰岛素治疗 3 个月。我们发现了一组独特的 miR 模式，这些 miR 在 HFpEF 患者中与健康对照组和 HFpEF 患者接受钠葡萄糖共转运蛋白 2（SGLT2）抑制剂恩格列净治疗相比，存在显著调节。与健康对照组相比，HFpEF 患者中有 3 个 miR（miR-126、miR-342-3p 和 miR-638）显著下调，2 个 miR（miR-21 和 miR-92）显著上调。值得注意的是，在 HFpEF 患者接受恩格列净治疗 3 个月后，其中 2 个 miR（miR-21 和 miR-92）显著降低，而接受二甲双胍或胰岛素治疗的患者内皮 miR 谱无显著差异。总之，我们的研究结果首次证明，与内皮功能调节相关的特定循环 miR 在虚弱的 HFpEF 合并糖尿病患者中存在显著调节，并对 SGLT2 抑制有反应。这些发现具有重要的临床意义，因为我们能够确定与疾病和治疗反应相关的新型生物标志物。
