Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart

Robert C Huebert, Qinglu Li, Neeta Adhikari, Nathan J. Charles, Xinqiang Han, Mohammed Karim Ezzat, Suzanne Grindle, Soon Park, Sofia Ormaza, David Fermin, Leslie W. Miller, Jennifer L. Hall

Research output: Contribution to journalArticle

24 Citations (Scopus)

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. Sprouty 1 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.

Original languageEnglish (US)
Pages (from-to)284-289
Number of pages6
JournalPhysiological Genomics
Volume18
DOIs
StatePublished - Oct 2004
Externally publishedYes

Fingerprint

Heart-Assist Devices
Up-Regulation
Endothelial Cells
Ventricular Remodeling
ras Genes
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Microvessels
Cardiac Myocytes
Muscle Cells
Vascular Endothelial Growth Factor A
Genes
Blood Vessels
Immunohistochemistry
Phosphorylation
Cell Proliferation
Messenger RNA
Proteins

Keywords

  • Genes
  • Heart failure
  • Molecular biology
  • Remodeling
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. / Huebert, Robert C; Li, Qinglu; Adhikari, Neeta; Charles, Nathan J.; Han, Xinqiang; Ezzat, Mohammed Karim; Grindle, Suzanne; Park, Soon; Ormaza, Sofia; Fermin, David; Miller, Leslie W.; Hall, Jennifer L.

In: Physiological Genomics, Vol. 18, 10.2004, p. 284-289.

Research output: Contribution to journalArticle

Huebert, RC, Li, Q, Adhikari, N, Charles, NJ, Han, X, Ezzat, MK, Grindle, S, Park, S, Ormaza, S, Fermin, D, Miller, LW & Hall, JL 2004, 'Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart', Physiological Genomics, vol. 18, pp. 284-289. https://doi.org/10.1152/physiolgenomics.00098.2004
Huebert, Robert C ; Li, Qinglu ; Adhikari, Neeta ; Charles, Nathan J. ; Han, Xinqiang ; Ezzat, Mohammed Karim ; Grindle, Suzanne ; Park, Soon ; Ormaza, Sofia ; Fermin, David ; Miller, Leslie W. ; Hall, Jennifer L. / Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart. In: Physiological Genomics. 2004 ; Vol. 18. pp. 284-289.
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