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

Cardiovascular Diabetology

Original Investigation

Abdulrahman L. Al-Malki¹  Sahira Lary¹  Sajjad Karim²  Adel M. Abuzenadah²  Adeel G. Chaudhary²  Mamdooh A. Gari²  Farid Ahmed²  Mohammed H. Alqahtani²  Hans-Juergen Schulten²  Ayat Bashir³  Sherin Bakhashab⁴  Fahad W. Ahmed⁵  Jolanta U. Weaver⁵ 

[1] Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia;Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia;Institute of Cellular Medicine, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK;Institute of Cellular Medicine, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK;Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia;Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia;Institute of Cellular Medicine, Newcastle University, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK;Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne, UK;

关键词: Hypoxia;    Hyperglycemia;    Angiogenesis;    CD34 stem cells;    Metformin;   

DOI  :  10.1186/s12933-016-0344-2

 received in 2015-12-29, accepted in 2016-01-26,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundCardiovascular 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.MethodsCD34+ 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.ResultsMetformin 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.ConclusionsMetformin 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.

【 授权许可】

CC BY   
© Bakhashab et al. 2016