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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Original investigation

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

Authors: Sherin Bakhashab, Fahad W. Ahmed, Hans-Juergen Schulten, Ayat Bashir, Sajjad Karim, Abdulrahman L. Al-Malki, Mamdooh A. Gari, Adel M. Abuzenadah, Adeel G. Chaudhary, Mohammed H. Alqahtani, Sahira Lary, Farid Ahmed, Jolanta U. Weaver

Published in: Cardiovascular Diabetology | Issue 1/2016

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
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Metadata
Title
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
Authors
Sherin Bakhashab
Fahad W. Ahmed
Hans-Juergen Schulten
Ayat Bashir
Sajjad Karim
Abdulrahman L. Al-Malki
Mamdooh A. Gari
Adel M. Abuzenadah
Adeel G. Chaudhary
Mohammed H. Alqahtani
Sahira Lary
Farid Ahmed
Jolanta U. Weaver
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0344-2

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