{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:01:35Z","timestamp":1783699295372,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medizinische Forschung (IMF)","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Innovative Medizinische Forschung (IMF)","award":["IZKF-SEED 014\/20"],"award-info":[{"award-number":["IZKF-SEED 014\/20"]}]},{"name":"Interdisziplin\u00e4re Zentrum f\u00fcr Klinische Forschung (IZKF)","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Interdisziplin\u00e4re Zentrum f\u00fcr Klinische Forschung (IZKF)","award":["IZKF-SEED 014\/20"],"award-info":[{"award-number":["IZKF-SEED 014\/20"]}]},{"name":"Deanery of the Medical Faculty of the University of M\u00fcnster","award":["GO121222"],"award-info":[{"award-number":["GO121222"]}]},{"name":"Deanery of the Medical Faculty of the University of M\u00fcnster","award":["IZKF-SEED 014\/20"],"award-info":[{"award-number":["IZKF-SEED 014\/20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNF\u03b1 signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNF\u03b1 expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NF\u03baB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NF\u03baB signalling in regulating SHP-2 expression, the elevated binding of NF\u03baB to the SHP-2 promoter\u2014induced by MG or AGE-BSA\u2014was reversed by RAGE and NF\u03baB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NF\u03baB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation.<\/jats:p>","DOI":"10.3390\/cells12030513","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T04:25:28Z","timestamp":1675657528000},"page":"513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacological Targeting of the RAGE-NF\u03baB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function"],"prefix":"10.3390","volume":"12","author":[{"given":"Marc","family":"Dorenkamp","sequence":"first","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madina","family":"Nasiry","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilvin","family":"Semo","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sybille","family":"Koch","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4982-5647","authenticated-orcid":false,"given":"Ivonne","family":"L\u00f6ffler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3291-0610","authenticated-orcid":false,"given":"Gunter","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Reinecke","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinesh","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Vascular Signalling, Molecular Cardiology, Department of Cardiology I\u2014Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"666","DOI":"10.3389\/fphar.2019.00666","article-title":"Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis","volume":"10","author":"Flynn","year":"2019","journal-title":"Front. 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