Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart
- 11 August 2004
- journal article
- research article
- Published by American Physiological Society in Physiological Genomics
- Vol. 18 (3), 284-289
- https://doi.org/10.1152/physiolgenomics.00098.2004
Abstract
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.Keywords
This publication has 32 references indexed in Scilit:
- A Role for the β-Catenin/T-Cell Factor Signaling Cascade in Vascular RemodelingCirculation Research, 2002
- Mammalian Sprouty Proteins Inhibit Cell Growth and Differentiation by Preventing Ras ActivationJournal of Biological Chemistry, 2001
- Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart FailureNew England Journal of Medicine, 2001
- Inhibition of Angiogenesis by a Mouse Sprouty ProteinJournal of Biological Chemistry, 2001
- From the Sarcomere to the Nucleus: Role of Genetics and Signaling in Structural Heart DiseaseAnnual Review of Genomics and Human Genetics, 2000
- A simple method for the rapid generation of recombinant adenovirus vectorsGene Therapy, 2000
- Activation of the Small GTP-binding Protein Ras in the Heart by Hypertrophic AgonistsTrends in Cardiovascular Medicine, 2000
- Ras and Rho are Required for Gαq-Induced Hypertrophic Gene Expression in Neonatal Rat Cardiac MyocytesJournal of Molecular and Cellular Cardiology, 1998
- Protein Kinase C, but Not Tyrosine Kinases or Ras, Plays a Critical Role in Angiotensin II-induced Activation of Raf-1 Kinase and Extracellular Signal-regulated Protein Kinases in Cardiac MyocytesJournal of Biological Chemistry, 1996
- Endothelin‐1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytesFEBS Letters, 1993