Identification and regulation of Sprouty1, a negative inhibitor of the ERK cascade, in the human heart.
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.
Lillehei Heart Institute, Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Robert C
RC
Huebert
Qinglu
Q
Li
Neeta
N
Adhikari
Nathan J
NJ
Charles
Xinqiang
X
Han
Mohammed-Karim
MK
Ezzat
Suzanne
S
Grindle
Soon
S
Park
Sofia
S
Ormaza
David
D
Fermin
Leslie W
LW
Miller
Jennifer L
JL
Hall
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006353:Heart-Assist Devices; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
D008565:Membrane Proteins; D010750:Phosphoproteins; C486055:SPRY1 protein, human