Modulating the functional contributions of c-Myc to the human endothelial cell cyclic strain response.
This study addresses whether pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction in human umbilical vein endothelial cells (HUVEC) or human aortic endothelial cells (HAEC). mRNA and protein expression of c-Myc under physiological (6-10%) and pathological cyclic strain conditions (20%) were studied. Both c-Myc mRNA and protein expression increased 2-3-fold in HUVEC cyclically strained at 20%. c-Myc protein increased 4-fold in HAEC. In HUVEC, expression of mRNA peaked at 1.5-2 h. Subsequently, the effect of modulating c-Myc on potential downstream gene targets was determined. A small molecular weight compound that binds to and stabilizes the silencer element in the c-Myc promoter attenuates cyclic strain-induced c-Myc transcription by about 50%. This compound also modulates c-Myc downstream gene targets that may be instrumental in induction of vascular disease. Cyclic strain-induced gene expression of vascular endothelial growth factor, proliferating cell nuclear antigen and heat shock protein 60 are attenuated by this compound. These results offer a possible mechanism and promising clinical treatment for vascular diseases initiated by increased cyclic strain.
Hurley
Nicole E
NE
Bioengineering Program, Georgia Institute of Technology, Atlanta, GA 30332-0535, USA.
Schildmeyer
Lisa A
LA
Bosworth
Kami A
KA
Sakurai
Yumiko
Y
Eskin
Suzanne G
SG
Hurley
Laurence H
LH
McIntire
Larry V
LV
D001665:Binding Sites; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D040542:Mechanotransduction, Cellular; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018834:Chaperonin 60; C489427:MYC protein, human; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A