Gene expression profiling of human stenotic aorto-coronary bypass grafts by cDNA array analysis.
OBJECTIVE
Aorto-coronary bypass graft disease with its increasing clinical signification represents an unsolved problem in cardiological and heart surgery practice. Late occlusion of autologous saphenous vein grafts is due to medial and neointimal thickening secondary to migration and proliferation of smooth muscle cells (SMCs) and the subsequent formation of atherosclerotic plaques. This study is aimed at identifying differentially expressed genes in human stenotic bypass grafts to detect unknown pathomechanism and to identify novel targets for prophylactic treatment options.


METHODS
Stenotic saphenous aorto-coronary bypass grafts (n=5) were retrieved during re-do aorto-coronary bypass surgery. Ungrafted saphenous vein segments (n=5) were taken from the same group of patients and served as internal controls. cDNA samples were prepared and hybridized to cDNA arrays.


RESULTS
Some of the differentially expressed genes complied with expected gene expression including upregulation of c-jun and CDK10. In addition, previously unidentified gene expression patterns were detected such as upregulation of HSP70, fibronectin1, erbB3 proto-oncogene and c-myc. To confirm the latter finding, upregulation of c-myc in neointimal and medial SMCs of stenotic graft segments was confirmed by in situ hybridization studies and by immunohistochemistry.


CONCLUSIONS
Gene expression patterns of human stenotic bypass grafts retrieved by re-do operations can be reliably analyzed by cDNA array technology. With this technique, new therapeutic targets in patients could be identified as shown by the findings regarding c-myc. c-myc is a proto-oncogene acting as a transcription factor and blocking c-myc has shown a reduction of neointima formation in animal models. Our study yields a rational for the use of antisense c-myc oligonucleotides to reduce neointima formation and to avoid stenosis in patients.
Hilker
Michael
M
Department of Thoracic and Cardiovascular Surgery, Johannes Gutenberg University, Mainz, Germany. hilker@mail.uni-mainz.de
Längin
Tina
T
Hake
Ulrich
U
Schmid
Franz-Xaver
FX
Kuroczynski
Wlodzimierz
W
Lehr
Hans-Anton
HA
Oelert
Helmut
H
Buerke
Michael
M
D000368:Aged; D001026:Coronary Artery Bypass; D023903:Coronary Restenosis / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D020893:Receptor, ErbB-3 / Q000235:genetics; D012086:Reoperation; D012501:Saphenous Vein
D005353:Fibronectins; D018840:HSP70 Heat-Shock Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D020893:Receptor, ErbB-3