Hyperglycaemia-induced methylglyoxal accumulation potentiates VEGF resistance of diabetic monocytes through the aberrant activation of tyrosine phosphatase SHP-2/SRC kinase signalling axis
| Autor: | Johannes Waltenberger, Marc Dorenkamp, Rinesh Godfrey, Kallipatti Sanjith Shanmuganathan, Ulrich Müller, Ivonne Löffler, Nicolle Müller, Jörg P. Müller, Gunter Wolf, Henny Schulten, Frank-D. Böhmer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A medicine.medical_specialty Phosphatase lcsh:Medicine Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase 030204 cardiovascular system & hematology Article Monocytes 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Animals Humans lcsh:Science Multidisciplinary Monocyte Chemotaxis lcsh:R Pyruvaldehyde Vascular endothelial growth factor 030104 developmental biology Endocrinology medicine.anatomical_structure src-Family Kinases chemistry Hyperglycemia Phosphorylation lcsh:Q Signal transduction Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-33014-9 |
| Popis: | Diabetes mellitus (DM) is a major cardiovascular risk factor contributing to cardiovascular complications by inducing vascular cell dysfunction. Monocyte dysfunction could contribute to impaired arteriogenesis response in DM patients. DM monocytes show blunted chemotactic responses to arteriogenic stimuli, a condition termed as vascular endothelial growth factor (VEGF) resistance. We hypothesize that methylglyoxal (MG), a glucose metabolite, induces monocyte dysfunction and aimed to elucidate the underlying molecular mechanisms. Human monocytes exposed to MG or monocytes from DM patients or mice (db/db) showed VEGF-resistance secondary to a pro-migratory phenotype. Mechanistically, DM conditions or MG exposure resulted in the upregulation of the expression of SHP-2 phosphatase. This led to the enhanced activity of SHP-2 and aided an interaction with SRC kinase. SHP-2 dephosphorylated the inhibitory phosphorylation site of SRC leading to its abnormal activation and phosphorylation of cytoskeletal protein, paxillin. We demonstrated that MG-induced molecular changes could be reversed by pharmacological inhibitors of SHP-2 and SRC and by genetic depletion of SHP-2. Finally, a SHP-2 inhibitor completely reversed the dysfunction of monocytes isolated from DM patients and db/db mice. In conclusion, we identified SHP-2 as a hitherto unknown target for improving monocyte function in diabetes. This opens novel perspectives for treating diabetic complications associated with impaired monocyte function. |
| Databáze: | OpenAIRE |
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