Papers by Sherin Bakhashab
Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patie... more 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 condi‑ tions 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 addition‑ ally ± 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 prom‑ ising 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.
G3: Genes|Genomes|Genetics, 2014
Human umbilical vein endothelial cell (HUVEC)-based gene expression studies carried out under hyp... more Human umbilical vein endothelial cell (HUVEC)-based gene expression studies carried out under hypoxia and/ or hyperglycemia bear huge potential in modelling endothelial cell response in cardiovascular disease and diabetes. However, such studies require reference genes that are stable across the whole range of experimental conditions. These reference genes have not been comprehensively defined to date. We applied human genome-wide microarrays and quantitative real-time PCR (qRT-PCR) on RNA obtained from primary HUVEC cultures that were incubated for 24 h either in euglycemic or hyperglycemic conditions and then subjected to short-term CoCl2-induced hypoxia of either 1, 3 or 12 h.
Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality
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Papers by Sherin Bakhashab