Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart
| Autor: | Sofia Ormaza, David Fermin, Nathan J. Charles, Robert C. Huebert, Soon J. Park, Leslie W. Miller, Neeta Adhikari, Mohammed Karim Ezzat, Suzanne Grindle, Qinglu Li, Xinqiang Han, Jennifer L. Hall |
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| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
Endothelium Physiology MAP Kinase Signaling System Biology Gene Expression Regulation Enzymologic Mice Downregulation and upregulation Chlorocebus aethiops Genetics medicine Myocyte Animals Humans Myocytes Cardiac Ventricular remodeling Regulation of gene expression Gene Expression Profiling Myocardium Membrane Proteins medicine.disease Phosphoproteins Cell biology Up-Regulation Endothelial stem cell medicine.anatomical_structure Animals Newborn Gene Expression Regulation COS Cells Cattle Endothelium Vascular Heart-Assist Devices Signal transduction |
| Zdroj: | Physiological genomics. 18(3) |
| ISSN: | 1531-2267 |
| Popis: | We screened a compendium of gene profiles from 19 paired human heart samples harvested at the time of implant and explant of a left ventricular assist device (LVAD) for novel genes regulating the Ras/MEK/ERK cascade. From this analysis we identified Sprouty1, an evolutionally conserved gene that acts as an intrinsic inhibitor of the Ras/MEK/ERK pathway. Sprouty1 mRNA and protein were significantly upregulated in the heart in response to mechanical unloading with a LVAD. The upregulation of Sprouty1 in the heart following mechanical unloading was accompanied by a significant decrease in phosphorylated ERK1/2. Gain of function experiments demonstrated that upregulation of Sprouty1 in isolated cardiac myocytes led to a significant decrease and altered kinetics of ERK1/2 phosphorylation. Immunohistochemistry of human hearts revealed that Sprouty1 was also expressed in the microvasculature. Upregulation of Sprouty1 in endothelial cells led to a significant decrease in VEGF-induced endothelial cell proliferation. To our knowledge, these findings are the first to define Sprouty expression in the heart and suggest that Sprouty1 may serve as an intrinsic mediator governing ventricular remodeling through a coordinated coupling of both myocyte and vascular alterations in response to mechanical load. |
| Databáze: | OpenAIRE |
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