Chronic administration of nano-sized PAMAM dendrimers in vivo inhibits EGFR-ERK1/2-ROCK signaling pathway and attenuates diabetes-induced vascular remodeling and dysfunction
| Autor: | Ibrahim F. Benter, Ahmed Z. El-Hashim, Mariam H. M. Yousif, Bindu Chandrasekhar, Waleed M. Renno, Saghir Akhtar |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Blood Glucose
Male Cell signaling Dendrimers EGFR Myocytes Smooth Muscle Biomedical Engineering Pharmaceutical Science Medicine (miscellaneous) Bioengineering 02 engineering and technology Pharmacology Vascular Remodeling Diabetes Mellitus Experimental 03 medical and health sciences Norepinephrine Polyamidoamine In vivo Diabetes mellitus medicine Animals General Materials Science Particle Size Rats Wistar Nano sized Extracellular Signal-Regulated MAP Kinases 030304 developmental biology 0303 health sciences rho-Associated Kinases Pamam dendrimers Chemistry Body Weight Diabetes Vascular complications 021001 nanoscience & nanotechnology medicine.disease Mesenteric Arteries ErbB Receptors Glucose Vasoconstriction Molecular Medicine Nanoparticles Signal transduction 0210 nano-technology Signal Transduction |
| Popis: | We investigated whether chronic administration of nano-sized polyamidoamine (PAMAM) dendrimers can have beneficial effects on diabetes-induced vascular dysfunction by inhibiting the epidermal growth factor receptor (EGFR)-ERK1/2-Rho kinase (ROCK)-a pathway known to be critical in the development of diabetic vascular complications. Daily administration of naked PAMAMs for up to 4 weeks to streptozotocin-induced diabetic male Wistar rats inhibited EGFR-ERK1/2-ROCK signaling and improved diabetes-induced vascular remodeling and dysfunction in a dose, generation (G6 > G5) and surface chemistry-dependent manner (cationic > anionic > neutral). PAMAMs, AG1478 (a selective EGFR inhibitor), or anti-EGFR siRNA also inhibited vascular EGFR-ERK1/2-ROCK signaling in vitro. These data showed that naked PAMAM dendrimers have the propensity to modulate key (e.g. EGFR) cell signaling cascades with associated pharmacological consequences in vivo that are dependent on their physicochemical properties. Thus, PAMAMs, alone or in combination with vasculoprotective agents, may have a beneficial role in the potential treatment of diabetes-induced vascular complications. This research is funded by a grant from the Research Sector at Kuwait University (MR01/13). We also acknowledge support from the OMICS Research Unit/RCF and the General Facility Grant (SRUL02/13). |
| Databáze: | OpenAIRE |
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