Metformin improves the angiogenic potential of human CD34⁺ cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction

• Published in: Cardiovascular diabetology Vol. 15; no. 1; p. 27
• Main Authors: Bakhashab, Sherin, Ahmed, Fahad W, Schulten, Hans-Juergen, Bashir, Ayat, Karim, Sajjad, Al-Malki, Abdulrahman L, Gari, Mamdooh A, Abuzenadah, Adel M, Chaudhary, Adeel G, Alqahtani, Mohammed H, Lary, Sahira, Ahmed, Farid, Weaver, Jolanta U
• Format: Journal Article
• Language: English
• Published: England BioMed Central 09.02.2016
• Subjects: Angiogenesis Inducing Agents - pharmacology; Antigens, CD34 - metabolism; Biomarkers - metabolism; Cell Hypoxia; Cells, Cultured; Chemokine CXCL10 - genetics; Chemokine CXCL10 - metabolism; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Profiling; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - immunology; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hyperglycemia - drug therapy; Hyperglycemia - genetics; Hyperglycemia - immunology; Hyperglycemia - metabolism; Hyperglycemia - physiopathology; Hypoglycemic Agents - pharmacology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metformin - pharmacology; Myocardial Infarction - drug therapy; Myocardial Infarction - immunology; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Neovascularization, Physiologic - drug effects; Original Investigation; Oxidoreductases - genetics; Oxidoreductases - metabolism; Phenotype; Stem Cells - drug effects; Stem Cells - immunology; Stem Cells - metabolism; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Up-Regulation; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-016-0344-2

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). To identify the most effective treatment for CVD, it is paramount to understand the mechanism behind cardioprotective therapies. Although metformin has been shown to reduce CVD in Type-2 DM clinical trials, the underlying mechanism remains unexplored. CD34(+) cell-based therapies offer a new treatment approach to CVD. The aim of this study was to investigate the effect of metformin on the angiogenic properties of CD34(+) cells under conditions mimicking acute myocardial infarction in diabetes. CD34(+) cells were cultured in 5.5 or 16.5 mmol/L glucose ± 0.01 mmol/L metformin and then additionally ± 4 % hypoxia. The paracrine function of CD34(+) cell-derived conditioned medium was assessed by measuring pro-inflammatory cytokines, vascular endothelial growth factor A (VEGFA), and using an in vitro tube formation assay for angiogenesis. Also, mRNA of CD34(+) cells was assayed by microarray and genes of interest were validated by qRT-PCR. Metformin increased in vitro angiogenesis under hyperglycemia-hypoxia and augmented the expression of VEGFA. It also reduced the angiogenic-inhibitors, chemokine (C-X-C motif) ligand 10 (CXCL10) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNAs, which were upregulated under hyperglycemia-hypoxia. In addition metformin, increased expression of STEAP family member 4 (STEAP4) under euglycemia, indicating an anti-inflammatory effect. Metformin has a dual effect by simultaneously increasing VEGFA and reducing CXCL10 and TIMP1 in CD34(+) cells in a model of the diabetic state combined with hypoxia. Therefore, these angiogenic inhibitors are promising therapeutic targets for CVD in diabetic patients. Moreover, our data are commensurate with a vascular protective effect of metformin and add to the understanding of underlying mechanisms.