ABSTRACT
Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.
Subject(s)
Diabetes Mellitus, Experimental , Endothelial Progenitor Cells , Glucagon-Like Peptides , Glucose , Immunoglobulin Fc Fragments , Mitochondrial Dynamics , Recombinant Fusion Proteins , Sirtuin 1 , Animals , Immunoglobulin Fc Fragments/pharmacology , Glucagon-Like Peptides/analogs & derivatives , Glucagon-Like Peptides/pharmacology , Glucagon-Like Peptides/therapeutic use , Sirtuin 1/metabolism , Mitochondrial Dynamics/drug effects , Endothelial Progenitor Cells/drug effects , Endothelial Progenitor Cells/metabolism , Recombinant Fusion Proteins/pharmacology , Male , Mice , Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Mice, Inbred C57BL , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Hypoglycemic Agents/pharmacology , Humans , Ischemia/metabolism , Ischemia/drug therapy , Ischemia/pathologyABSTRACT
OBJECTIVE: Based on cell model and HPLC-MS technology, to screen myocardial protection active compounds from traditional patent medicine Tongmai Yangxin pill (TMYXP). METHODS: Fractions of TMYXP were prepared by high performance liquid preparation technology. The cardioprotective effects of prepared fractions were tested on H2O2 oxidation-damaged H9c2 myocardiocytes. The active components were analyzed by high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. The possible active compounds were putatively identified by comparison of their MS ions and molecular weight with literatures. RESULTS: Ten TMYXP components presented significant myocardial protective activities, 5 of which were investigated and presented good dose-effect relationships. Their median effective concentrations (EC50) were respectively 11.66, 17.44, 13.10, 7.332, 15.15 µg/mL. Totally, 11 potential active compounds were analyzed and identified, including Glycyrrhizic acid, Glycycoumarin, Licoisoflavone, Ophiopogonin D', Licoricon, Gancaonin L, Neoglycyrol, Emodin, Angeloylgomisin H, Angeloylgomisin Q and Glyasperin A. CONCLUSION: The myocardial protection active compounds of TMYXP were screened successfully.
