Transcriptional control of cardiac allograft vasculopathy by early growth response gene-1 (Egr-1).
Expression of the zinc finger transcription factor early growth response gene-1 (Egr-1) is triggered rapidly after mechanical vascular injury or after a precipitous drop in ambient oxygen, whereupon it induces the expression of diverse gene families to elicit a pathological response. Initially characterized as an early response transcriptional activator, the role of Egr-1 in more chronic forms of vascular injury remains to be defined. Studies were designed to examine whether Egr-1 induction may serve as a causal link between early preservation injury and delayed vascular consequences, such as coronary allograft vasculopathy (CAV). The preservation and transplantation of heterotopic murine cardiac allografts strongly induce Egr-1 expression, leading to increased expression of its downstream target genes, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet-derived growth factor A chain. Expression of these Egr-1-inducible gene targets is virtually obliterated in homozygous Egr-1-null donor allografts, which also exhibit attenuated parenchymal rejection and reduced CAV as long as 60 days. Congruous data are observed by treating donor hearts with a phosphorothioate antisense oligodeoxyribonucleotide directed against Egr-1 before organ harvest, which blocks subsequent expression of Egr-1 mRNA and protein and suppresses the late development of CAV. These data indicate that Egr-1 induction represents a central effector mechanism in the development of chronic rejection characterized by CAV. Blocking the expression of this proximal transcription factor solely at the time of organ harvest elicits beneficial delayed consequences for the cardiac allograft.
Okada
Morihito
M
College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Wang
Catherine Y
CY
Hwang
Daniel W
DW
Sakaguchi
Taichi
T
Olson
Kim E
KE
Yoshikawa
Yasushi
Y
Minamoto
Kanji
K
Mazer
Sean P
SP
Yan
Shi-Fang
SF
Pinsky
David J
DJ
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006133:Growth Substances / Q000378:metabolism; D016027:Heart Transplantation; D017874:Immediate-Early Proteins; D007518:Isoantibodies / Q000276:immunology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000032:analysis / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006133:Growth Substances; D017874:Immediate-Early Proteins; D007518:Isoantibodies; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors