Abstract
Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34+ cells under hyperglycemia-hypoxia. Now we studied the direct effect of physiological dose of metformin on human umbilical vein endothelial cells (HUVEC) under conditions mimicking hypoxia-hyperglycemia. HUVEC migration and apoptosis were studied after induction with euglycemia or hyperglycemia and/or CoCl2 induced hypoxia in the presence or absence of metformin. HUVEC mRNA was assayed by whole transcript microarrays. Genes were confirmed by qRT-PCR, proteins by western blot, ELISA or flow cytometry. Metformin promoted HUVEC migration and inhibited apoptosis via upregulation of vascular endothelial growth factor (VEGF) receptors (VEGFR1/R2), fatty acid binding protein 4 (FABP4), ERK/mitogen-activated protein kinase signaling, chemokine ligand 8, lymphocyte antigen 96, Rho kinase 1 (ROCK1), matrix metalloproteinase 16 (MMP16) and tissue factor inhibitor-2 under hyperglycemia-chemical hypoxia. Therefore, metformin’s dual effect in hyperglycemia-chemical hypoxia is mediated by direct effect on VEGFR1/R2 leading to activation of cell migration through MMP16 and ROCK1 upregulation, and inhibition of apoptosis by increase in phospho-ERK1/2 and FABP4, components of VEGF signaling cascades.
Highlights
Cardiovascular disease (CVD) remains the leading cause of death worldwide according to the World Health Organization 2016 mortality database
The outcome of CVD management is affected by diabetes mellitus (DM), which results in a two- to four-fold increased risk of CVD [1,2]
We have shown that physiological concentrations of metformin improved endothelial cell (EC) survival and migration under hyperglycemia-chemical hypoxia through activation of vascular endothelial growth factor (VEGF) signaling pathway
Summary
Cardiovascular disease (CVD) remains the leading cause of death worldwide according to the World Health Organization 2016 mortality database. The outcome of CVD management is affected by diabetes mellitus (DM), which results in a two- to four-fold increased risk of CVD [1,2]. Diabetes associated endothelial dysfunction is a known early step in the adverse sequence of events leading to the development of micro- and macrovascular complications, which results in mortality linked to diabetes in 75% of cases [5]. Vascular complications include both qualitative and quantitative changes in vascular architecture, in particular: abrogation of neovascularization and remodeling of the existing vasculature that results in a lack of ability to control ischemic injury. When used in patients with metabolic syndrome, post-PCI myocardial injury was improved [8]
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