Sustained activation of p38 mitogen-activated protein kinase contributes to the vascular response to injury
| Autor: | Marinella Berova, Robert N. Willette, Alan R. Olzinski, Haisong Ju, John C. Lee, Rosanna C. Mirabile, Joseph Sisko, Sandhya S. Nerurkar, Charles F. Sauermelch, Dawn Zimmerman, Jerry L. Adams |
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| Rok vydání: | 2002 |
| Předmět: |
MAPK/ERK pathway
Neointima Male Vascular smooth muscle medicine.medical_treatment p38 mitogen-activated protein kinases Blotting Western Hypercholesterolemia p38 Mitogen-Activated Protein Kinases Muscle Smooth Vascular Substrate Specificity Cell Movement medicine Animals Protein kinase A Cells Cultured Pharmacology biology Neovascularization Pathologic Growth factor Imidazoles Immunohistochemistry Cell biology Fibronectins Enzyme Activation Pyrimidines Immunology biology.protein Molecular Medicine Blood Vessels Rabbits Mitogen-Activated Protein Kinases Platelet-derived growth factor receptor Angioplasty Balloon Cell Division Transforming growth factor |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 301(1) |
| ISSN: | 0022-3565 |
| Popis: | The vascular response to mechanical injury involves inflammatory and fibroproliferative processes that result in the formation of neointima and vascular remodeling. The complex cellular interactions initiated by vascular injury are coordinated and modulated by the elaboration of cytokines and growth factors. The production and transduction of many of these mediators require phosphorylation of p38 mitogen-activated protein kinase (MAPK). In the present investigation, we examined the pattern and localization of p38 MAPK activation following balloon vascular injury. The effects of long-term and selective inhibition of p38 MAPK with SB 239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-methoxy)pyrimidin-4-yl]imidazole) were also investigated in a model of vascular injury. Western blotting and immunohistochemical staining demonstrated that phospho-p38 MAPK was increased following balloon injury of the rabbit iliofemoral artery. The p38 MAPK activation was noted as early as 15 min after balloon injury and remained elevated for at least 28 days. Phospho-p38 MAPK immunoreactivity (IR) was localized primarily in regions of dedifferentiated, smooth muscle alpha-actin-positive cells in all lamina of the vessel wall. Phospho-p38 MAPK IR was not correlated with the localization of macrophage or proliferating cells (proliferating cell nuclear antigen; PCNA +). Long-term treatment (4 weeks) with SB 239063 (50 mg/kg/day, p.o.) reduced the vascular response to injury in the hypercholesterolemic rabbit. SB 239063 had no effect on platelet-derived growth factor (PDGF)-stimulated migration or proliferation of rabbit vascular smooth muscle cells (VSMCs) in culture. However, SB 239063 produced a concentration-dependent inhibition of transforming growth factor (TGF)-beta-stimulated fibronectin production in VSMCs. In conclusion, sustained activation of p38 MAPK plays an important role in the vascular response to injury and inhibition of p38 MAPK may represent a novel therapeutic approach to limit this response. |
| Databáze: | OpenAIRE |
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